Resistance-repellent retroviral protease inhibitors

ABSTRACT

Resistance-repellent and multidrug resistant retroviral protease inhibitors are provided. Pharmaceutical composition comprising such compounds, and methods of using such compounds to treat HIV infections in mammals, are also provided.

This application claims priority to Provisional Application No.60/568,935, filed May 7, 2004.

The present invention relates to retroviral protease inhibitors and,more particularly, relates to novel compounds, compositions and methodsfor inhibiting retroviral proteases. This invention, in particular,relates to resistance-repellent HIV protease inhibitors, compositions,and uses thereof for treating HIV infections, particularly infectionscaused by one or more species of drug resistant HIV strains. Theinvention further provides compounds that are resistant to degradationin vivo and that inhibit degradation of other protease inhibitors.

BACKGROUND OF THE INVENTION

Acquired immune deficiency syndrome (AIDS) is a fatal disease, reportedcases of which have increased dramatically within the past severalyears. Estimates of reported cases in the very near future also continueto rise dramatically. Consequently, there is a great need to developdrugs and vaccines to combat AIDS.

The AIDS virus was first identified in 1983. It has been known byseveral names and acronyms. It is the third known T-lymphocyte virus(HTLV-III), and it has the capacity to replicate within cells of theimmune system, causing profound cell destruction. The AIDS virus is aretrovirus, a virus that uses reverse transcriptase during replication.This particular retrovirus is also known as lymphadenopathy-associatedvirus (LAV), AIDS-related virus (ARV) and, most recently, as humanimmunodeficiency virus (HIV). Two distinct families of HIV have beendescribed to date, namely HIV-1 and HIV-2. The acronym HIV is usedhereinafter to refer to HIV viruses generically.

Specifically, HIV is known to exert a profound cytopathic effect on CD4+helper/inducer T-cells, thereby severely compromising the immune system.HIV infection also results in neurological deterioration and,ultimately, in the death of the infected individual.

The field of viral chemotherapeutics has developed in response to theneed for agents effective against retroviruses, in particular HIV.Theoretically, there are many ways in which an agent can exhibitanti-retroviral activity. The HIV genome encodes several viral-specificenzymes, such as reverse transcriptase (RT), integrase and protease(PR); viral-specific regulatory proteins, such as tat, rev, nef and vif;and, numerous viral-specific structural proteins, and numerousviral-specific structural proteins, such as capsid, nucleocapsid,matrix, and envelope proteins. Many of these proteins are essential forviral replication. Accordingly, viral replication theoretically could beinhibited through inhibition of any one or all of the proteins involvedin viral replication. In practice, however, only inhibitors of RT and PRare currently available for antiviral therapy.

Nucleoside analogues (NRTIs), such as 3′-azido-2′,3′-dideoxythymidine(AZT), 2′,3′-dideoxycytidine (ddC), and 2′,3′-dideoxyinosine (ddI) areknown to inhibit HIV RT. There also exist non-nucleoside inhibitors(NNRTIs) specific for HIV-1 RT, such as Nevirapine, and Efavirenz.

Retroviral PR inhibitors (PIs) have also been identified as a class ofanti-retroviral agents. The retroviral PR processes polyproteinprecursors into viral structural proteins and replicative enzymes. Thisprocessing is essential for the assembly and maturation of fullyinfectious virions. Accordingly, the design of PIs that selectivelyinhibit PR has been an important therapeutic goal in the treatment ofHIV infections and AIDS. Strategies used in the design of HIV PIsinclude substrate-based, peptidomimetic, transition state-based, andstructure-based drug design (Wlodawer & Erickson, Ann. Rev. Biochem.,62, 543-585 (1992)).

Numerous classes of potent peptidic inhibitors of PR have been designedusing the natural cleavage site of the precursor polyproteins as astarting point. These inhibitors typically are peptide substrate analogsin which the scissile P1-P1′ amide bond has been replaced by anon-hydrolyzable isostere with tetrahedral geometry (Moore et al.,Perspect. Drug Dis. Design, 1, 85 (1993); Tomasselli et al., Int. J.Chem. Biotechnology, 6 (1991); Huff, J. Med. Chem., 34, 2305 (1991);Norbeck et al., Ann. Reports Med. Chem., 26, 141 (1991); Meek, J. EnzymeInhibition, 6, 65 (1992)).

The design of HIV-1 PIs based on the transition-state mimetic concepthas led to the generation of a variety of peptide derivatives highlyactive against viral replication in vitro (Erickson et al., Science;249, 527-533 (1990); Kramer et al., Science, 231, 1580-1584 (1986);McQuade et al., Science, 247, 454-456 (1990); Meek et al., Nature(London), 343, 90-92 (1990); Roberts et al., Science, 248, 358-361(1990)). These active agents contain a non-hydrolyzable, dipeptideisostere such as hydroxyethylene (McQuade et al., supra; Meek et al.,Nature (London), 343, 90-92 (1990); Vacca et al., J. Med. Chem., 34,1225-1228 (1991)) or hydroxyethylamine (Rich et al., J. Med. Chem., 33,1285-1288 (1990); Roberts et al., Science, 248, 358-361 (1990)) as anactive moiety which mimics the putative transition state of the asparticprotease-catalyzed reaction.

Two-fold (C2) symmetric inhibitors of HIV protease represent anotherclass of potent HIV PIs which were created by Erickson et al. on thebasis of the three-dimensional symmetry of the enzyme active site(Erickson et al., supra).

Typically, the usefulness of currently available HIV PIs in thetreatment of AIDS has been limited by relatively short plasma half-life,poor oral bioavailability, and the technical difficulty of scale-upsynthesis (Meek et al. (1992), supra). Although these inhibitors areeffective in preventing the retroviral PR from functioning, theinhibitors suffer from some distinct disadvantages. Generally,peptidomimetics make poor drugs due to their potential adversepharmacological properties, i.e., poor oral absorption, poor stabilityand rapid metabolism (Plattner et al., Drug Discovery Technologies,Clark et al., eds., Ellish Horwood, Chichester, England (1990)).Furthermore, since the active site of the PR is hindered, i.e., hasreduced accessibility as compared to the remainder of the PR, theability of the inhibitors to access and bind in the active site of thePR is impaired. Those inhibitors that do bind are generally poorlywater-soluble, causing distinct problems for formulation and drugdelivery.

There are currently six FDA-approved PIs for clinical use—Saquinavir,Ritonavir, Indinavir, Nelfinavir, Amprenavir and Lopinavir. When usedalone or in combination with RT inhibitors, PIs dramatically suppressviral replication in HIV-infected individuals. Accordingly, PIs havebecome “first-line” antiviral agents for the control of HIV-1 (HIV)infections and are widely used in most highly active anti-retroviraltherapy (HAART) regimens (Boden & Markowitz, Antimicrob. Agents Chemo.,42, 2775-2783, (1998)). Despite their success, the widespread use of PIshas led to the emergence of several thousands of genetically distinct,drug resistant HIV variants, many of which are cross-resistant to thePIs as a class (Richman, Adv. Exp. Med. Biol., 392, 383-395 (1996);Boden & Markowitz (1998), supra; Shafer et al. Ann. Intern. Med., 128,906-911(1998)).

The ability of HAART to provide effective long-term antiretroviraltherapy for HIV-1 infection has become a complex issue since 40 to 50%of those who initially achieve favorable viral suppression toundetectable levels experience treatment failure (Grabar et al., AIDS,14, 141-149 (1999); Wit et al., J. Infect. Dis., 179, 790-798 (1999)).Moreover, 10 to 40% of antiviral therapy-naive individuals infected withHIV-1 have persistent viral replication (plasma HIV RNA>500 copies/ml)under HAART (Gulick et al., N. Engl. J. Med., 337, 734-739 (1997);Staszewski et al., N. Engl. J. Med., 341, 1865-1873 (1999)), possiblydue to transmission of drug-resistant HIV-1 variants (Wainberg andFriedland, JAMA, 279, 1977-1983 (1998)). In addition, it is evident thatwith these anti-HIV drugs only partial immunologic reconstitution isattained in patients with advanced HIV-1 infection.

The clinical manifestations of drug resistance are viral RNA rebound anddecreased CD4 cell-counts in the continued presence of drug. Themajority of clinical resistance cases are due to viral adaptationthrough the generation and selection of mutations in the PR and RTgenes. Mutant viruses can be generated through errors in reversetranscription of viral RNA, viral RNA synthesis, and recombinationevents (Coffin, Retroviruses pp. 143-144, Cold Spring Harbor LaboratoryPress, Plainview (1997)). Mutations within the protease gene that conferclinical drug resistance have emerged for all of the FDA-approved HIV PRinhibitors. The rapid development of drug resistance to PIs, combinedwith the transmissibility of drug-resistant HIV strains tonewly-infected individuals, has resulted in the emergence of a newepidemic of multi-drug resistant AIDS (mdrAIDS). Multi-drug resistantAIDS is caused by a complex spectrum of genetically distinct, infectiousnew HIV strains that resist most or all forms of currently availabletreatment.

Accordingly, drug resistant HIV strains represent distinct infectiousentities from a therapeutic viewpoint, and pose new challenges for drugdesign as well as drug treatment of existing infections. Substitutionshave been documented in over 45 of the 99 amino acids of the HIVprotease monomer in response to protease inhibitor treatment—(Mellors,et al., International Antiviral News, 3, 8-13(1995); Eastman, et al., J.Virol., 72, 5154-5164(1998); Kozal, et al., Nat. Med., 2,753-759(1996)). The particular sequence and pattern of mutationsselected by PIs is believed to be somewhat drug-specific and oftenpatient-specific, but high level resistance is typified by multiplemutations in the protease gene which give rise to cross-resistance toall of the PIs.

The challenge of tackling drug resistance is perhaps best illustrated byconsidering the dynamics of a typical HIV infection. Approximately 10¹²virions are produced in an HIV infected individual every day. Themutation rate of HIV is approximately 1 per genome, which numbers 10⁴nucleotide bases. Therefore, every nucleotide in the genome is mutated10⁸ times per round of replication in the patient. This means that allpossible single site mutations are present in at least the 0.01% level.Because of this, drugs that can be rendered ineffective with a singlemutation from wild type have the shortest effective lifetime inmonotherapy settings. The apparently large number of possible mutationalpathways, possible mutational combinations, and the danger of generatingclass-specific cross resistance can make the choice of a subsequentprotease inhibitor-containing-combination regimen for “salvage therapy”seem very complicated and risky. Even the choice of protease inhibitorwith which to initiate therapy, so-called “first-line” therapy, can be arisky enterprise that may inadvertently select for an undesiredresistance pathway. Drug-naïve HIV-infected individuals pose even moreof a risk for developing resistance to first-line therapies.

For the reasons outlined above, the development of new anti-HIV-1therapeutics presents formidable challenges different from those in thedesign of the first line drugs, particularly in regard to considerationof selection pressure mechanisms in addition to the conventional issuesof potency, pharmacology, safety, and mechanism of drug action. Indeed,HIV-1 can apparently develop resistance to any existing anti-HIV-1therapeutic. In particular, the very features that contribute to thespecificity and efficacy of RTIs and PIs provide the virus with astrategy to mount resistance (Erickson and Burt, Annu. Rev. Pharmacol.Toxicol., 36, 545-571 (1996); Mitsuya and Erickson, Textbook of AIDSMedicine, pp. 751-780, Williams and Wilkins, Baltimore (1999)), and itseems highly likely that this resistance issue will remain problematicfor years to come.

Despite numerous studies of drug resistance to PIs, successfulstrategies to design inhibitors directly targeted against drug resistantHIV have been lacking. Instead, efforts have been directed atidentifying drugs with increased potency to wild type virus, and withlonger pharmacological half-lives (exemplified by Amprenavir). Anotherapproach has been to develop PIs that are sensitive to pharmacologic“boosting” using Ritonavir, a PI that is also a potent inhibitor of thecytochrome enzymes. The latter approach is exemplified by Kaletra (aLopinavir/Ritonavir combination). Several other PIs have been identifiedbased on efforts to improve plasma half-life and bioavailability. Forexample, PIs incorporating the2,5-diamino-3,4-disubstituted-1,6-diphenylhexane isostere are describedin Ghosh et. al., Bioorg. Med. Chem. Lett., 8, 687-690 (1998) and U.S.Pat. No. 5,728,718 (Randad et al.), both of which are incorporatedherein by reference in their entirety. HIV PIs, which incorporate thehydroxyethylamine isostere, are described in U.S. Pat. No. 5,502,060(Thompson et al.), U.S. Pat. No. 5,703,076 (Talley et al.), and U.S.Pat. No. 5,475,027 (Talley et al.).

Recent studies have revealed the structural and biochemical mechanismsby which mutations in the PR gene of HIV confer drug resistance in thepresence of PIs. An important conclusion that emerges from the body ofevidence on resistance to PIs is that HIV variants that exhibitcross-resistance to first-line PIs should be considered to be uniqueinfectious agents. New therapeutic agents need to be developed tosuccessfully treat patients infected with these viruses. New strategiesfor drug discovery need to be explored to develop effective proteaseinhibitor-based treatments for patients with multidrug resistant virus.HIV protease is one the most intensively studied molecular targets inthe history of infectious disease.

More recently, new mutant strains of HIV have emerged that are resistantto multiple, structurally diverse, experimental and chemotherapeutic HIVPIs. Such mdrHIV strains are typically found in infected patients whohave undergone treatment with a combination of PIs or with a series ofdifferent PIs. The number of reported cases of patients infected withmdrHIV is rising steadily. Tragically for these patients, the availableoptions for AIDS chemotherapy and/or HIV management is severely limitedor is, otherwise, completely nonexistent.

A biochemical fitness profiling strategy has recently been used toidentify a novel subclass of potent PIs that have broad-based activityagainst mdrHIV (Gulnik et al., (1995) supra; Erickson et al., WO99/67254; Erickson et al., WO 99/67417).

In view of the foregoing problems, there exists a need for inhibitorsagainst drug resistant and mdrHIV strains. Further, there exists a needfor inhibitors against drug resistant and multi-drug resistant HIVproteases (mdrPR). Further still, there exists a need for inhibitors ofHIV that can prevent or slow the emergence of drug resistant and mdrHIVstrains in infected individuals. Inhibitors with the ability to inhibitmdrHIV strains, and to slow the emergence of drug resistant strains inwild type HIV infections, are defined as “resistance-repellent”inhibitors. There also exists a need for robust methods that can be usedto design “resistance-repellent” inhibitors.

SUMMARY OF THE INVENTION

The present invention provides such resistance-repellent inhibitors ofmdrPR, their compositions, methods of design, and uses thereof fortreating mdrHIV and wtHIV infections in salvage therapy and first-linetherapy modalities.

More particularly, the invention provides HIV protease inhibitorsrepresented by the formula I:X-A-B-A′-X′  I

where X is a moiety that contains two or more hydrogen bond acceptorscapable of interacting with the backbone NH atoms of residues 29 and 30of an HIV protease, A is a 2-6 atom linker that contains at least onehydrogen bond acceptor that interacts with the flap water, and onehydrogen bond donor that interacts with the backbone CO atom of residue27, B contains 1-3 atoms that can form hydrogen bonds with either orboth carboxylate side chain oxygens of Asp25 and Asp 125 of saidprotease, A′ is a 2-6 atom linker that contains at least one hydrogenbond acceptor that interacts with the flap water; and X′ is a moietythat can form one or more hydrogen bonds with the backbone NH atoms ofresidues 129 and/or 130, provided that the compound of Formula I is notany of the compounds described in J. Med. Chem. 39:3278-3290 (1996), inBioorg. Med. Chem. Lett. 8:687-690 (1998), or Bioorg. Med. Chem. Lett.8:979-982 (1998).

The invention also provides a compound as described above, bound in acomplex with wild type or drug resistant mutant forms of HIV-1 protease.

The invention further provides pharmaceutical compositions, comprisingan inhibitor as described above, together with a pharmaceuticallyacceptable additive, excipient, or diluent. The composition may furthercomprise an additional HIV protease inhibitor and/or an HIV reversetranscriptase inhibitor.

Specifically, the invention provides an HIV protease inhibitorrepresented by a formula:X-A-B-A′-X′

where:

X is a 5-7 membered non-aromatic monocyclic heterocycle, where theheterocycle is optionally fused or bridged with one or more 3-7 memberednon-aromatic monocyclic heterocycle to form a polycyclic system, whereany of the heterocyclic ring systems contains one or more heteroatomsselected from O, N, S, or P; where any nitrogen forming part of theheterocycles may optionally be substituted by R2, R3, R6, R7 or O; whereany sulfur may optionally be substituted by one or two oxygen atoms;where any P may optionally be substituted by one or more of O, NR2, orS, and any of the ring systems optionally contains 1 to 6 substituentsselected from the group consisting of R2, R3, R5, and R6;

A is ZCZNH, ZCOCONH, ZS(O)₂NH, ZP(O)(V)NH, CONH, COCONH, S(O)₂NH,P(O)(V)NH, where Z is NR2, O, S, or C(R2)₂, and V is OR2 or NR2;

B is

where D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oraralkyl optionally substituted with one or more groups selected fromalkyl, halo, nitro, cyano, CF₃, C3-C7 cycloalkyl, C5-C7 cycloalkenyl,R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6;

A′ is N(D′)E′, where D′ is selected from alkyl, alkenyl, alkynyl, aryl,cycloalkyl, or aralkyl optionally substituted by alkyl, halo, nitro,cyano, CF₃, O-alkyl, or S-alkyl, and E′ is —CO— or —SO₂—;

X′ is

where G1 is NH or O;

where G2 is CZ″ or N;

where Z″ is selected from the group consisting of halogen, R2, R3, orR6;

where Z′″ is selected from the group consisting of H or R2, R3, R6,halo, haloalkyl, C(R2)₂OR, C(R2)₂COR, C(R2)₂OCOR, C(R2)₂CO₂R,C(R2)₂N(R)₂, C(R2)₂SR, C(R2)₂SOR, C(R2)₂SO₂R, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

where X′ is optionally substituted with one or more substituents, eachindependently selected from (a)-(h) as follows:

(a) OR3, OR6, OR7, OR2;

(b) alkyl substituted by R3, R5, R6;

(c) C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl,and heterocyclyl, which groups may be optionally substituted with one ormore substituents selected from R5;

(d) aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, R4 and R6;

(e) C3-C7 cycloalkyl substituted by R2, R3, R5 or R6;

(f) CO₂H or R7;

(g) NR8R8, NR7R8, NR7R7; and

(h) SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8; and n is 1 or 2;

R is H or is selected from the group consisting of alkyl, aryl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and heteroaryl;optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy,heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino,or mono- or dialkylamino, mono- or diarylamino, mono- ordi-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl,cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- ordialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- ordialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;

R2 is H or C1-C6 alkyl; optionally substituted by C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)NR, N(R)₂,N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR;

or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo,NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R,N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8cycloalkenyl, or heterocyclo; which groups may be optionally substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, oxo, ═N—OR2,═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂,or ═NNR2S(O)_(n)(R2);

R4 is selected from the group consisiting of halo, OR8, R2-OH, R3-OH,R2-halo, R3-halo, NO₂, CN, CO_(n)R8, CO_(n)R8, CON(R8)₂,C(O)N(R8)N(R8)₂, C(S)R8, C(S)N(R8)₂, SO_(n)N(R8)₂, SR8, SO_(n)R8,N(R8)₂, N(R8)CO_(n)R8, NR8S(O)_(n)R8, NR8C[═N(R8)₂, N(R8)N(R8)CO_(n)R8,NR8PO_(n)N(R8)₂, NR8PO_(n)OR8, OC(O)R2, OC(S)R8, OC(O)N(R8)₂,OC(S)N(R8)₂ and OPO_(n)(R8)₂;

R5 is selected from the group consisting of OR8, N(R8)₂, NHOH,N(R8)COR8, NR8S(O)_(n)R8, NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)C(O)R8,NR8PO_(n)N(R8)₂, NR8PO_(n)OR8, R2OH, R3-OH, R2-halo, R3-halo, CN,CO_(n)R8; CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)_(n)R8, C(S)N(R8)₂, S(O)_(n)R8,SO_(n)N(R8)₂, halo, NO₂, SR8, oxo, ═N—OH, ═N—OR8, ═N—N(R8)₂, ═NR8,═NNR8C(O)N(R8)₂, ═NNR8C(O)_(n)R8, ═NNR8S(O)_(n)N(R8)₂, or═NNR8S(O)_(n)(R8) and R3;

R6 is aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from aryl, heteroaryl, R2,R3, halo, OR2, R2OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, OC(S)N(R2)₂, OPO_(n)(R2)₂,

R7 is selected from the group consisting of C(O)_(n)R8; C(S)R8,C(O)N(R8)₂, C(S)N(R8)₂, S(O)_(n)R8 and S(O)nN(R8)₂;

R8 is R2, R3, or R6;

R9 is alkyl optionally substituted by R3, R5, R6; C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and heterocyclo, whichgroups may be optionally substituted with one or more substituentsselected from the group consisting of —OR2, C(O)N(R2)₂, S(O)_(n)N(R2)₂,CN, SR2, SO_(n)R2, COR2, CO₂R2 or NR2C(O)R2, R5, and R7; aryl orheteroaryl, where the aryl or heteroaryl may be optionally substitutedwith one or more groups selected from the group consisting of aryl,heteroaryl, R2, R3, R4, and R6; C3-C7 cycloalkyl optionally substitutedby R2, R3, R5, R6; CO₂H or R7; NR3R3, NR6R6, NR7R7, NR3R6, NR6R7, NR3R7,NR2R3, NR2R6, NR2R7, NR2R2; SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8,and n is 1 or 2; SO_(n)N(R2)₂, SO_(n)N(R3)₂, SO_(n)N(R6)₂, SO_(n)N(R7)₂,SO_(n)NR2R3, SO_(n)NR2R6, SO_(n)NR2R7, SO_(n)NR3R6, SO_(n)NR3R7,SO_(n)NR6R7; S(O)_(m)R2, S(O)_(m)R3, S(O)_(m)R6; and m is 0, 1 or 2; andeach n is independently 1 or 2.

In one embodiment,

X is

Y is O, NH, or S;

Z is O, NH, or S; and

any ring carbon many optionally be substituted by R2, R3, R5, or R6.

In another embodiment, X is

where

G is C, O, NR2,or S;

n is an integer between 1-2; and

any ring carbon may optionally be substituted by R2, R3, R5, or R6.

In yet another embodiment, X is

where

J is independently CH₂, or O and

where any ring carbon may optionally be substituted by R2, R3, R5, orR6.

In still another embodiment, X is

where any ring carbon may optionally be substituted by R2, R3, R5, orR6.

In another embodiment, X is

where each L is independently H, lower alkyl, oxo, or L forms acarbocyclic or heterocyclic ring with M;

each M is independently H, OH, chloro, fluoro, or M forms a carbocyclicor heterocyclic ring with Q, provided that if one M is OH, the other Mis not OH;

Q is H, OH, amino, lower alkyl, alkylamino, alkoxy, halo, or forms a3-7-membered carbocyclic or heterocyclic ring together with T;

each F is independently H, OH, lower alkyl, halo, or spirocylopropyl,provided that if one R is OH, the other R is not OH; and

T is H or F, or T forms a carbocyclic or heterocyclic ring together withF.

In a particular embodiment, Xis tetrahydrofurodihydrofuranyl,tetrahydrofurotetrahydrofuranyl, tetrahydropyranotetrahydrofuranyl ortetrahydropyranodihydrofuranyl;

A is OCONH;

B is

where D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oraralkyl optionally substituted with one or more groups selected fromalkyl, halo, nitro, cyano, CF₃, C3-C7 cycloalkyl, C5-C7 cycloalkenyl,R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6; and

A′ is N(D′)E′, where D′ is alkyl, alkenyl, alkynyl aryl, cycloalkyl, oraralkyl optionally substituted by alkyl, halo, or CF₃, and E′ is —SO₂—.

In still another embodiment, X is tetrahydrofurotetrahydrofuranyl;

A is OCONH;

B is

where D is benzyl; and

A′ is N(D′)E′, where D′ is isobutyl and E′ is —SO₂—;

In another embodiment, X is

where A2, B2, and C′ are each independently O, NR2, or S;

D2 is CH or N; and

n is an integer between 1 and 2.

Alternatively, X is

where

A3 is H, F or alkoxy;

B3 is F, alkoxy, lower alkyl, or A3 and B3 can form a 3-7 memberedheterocyclic ring;

Z′ is O, NR2, or S; and

n is an integer between 1-3.

In other embodiments, X′ is selected from

where the groups are optionally substituted with one or more of thefollowing groups:

oxo, halo, OR3, OR6, OR7, OR2 provided R2 is not H or unsubstitutedalkyl;

alkyl optionally substituted by R3, R5, R6 provided R5 is not halo;

C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, andheterocyclo, which groups may be optionally substituted with one or moresubstituents selected from R5;

aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, R4, and R6;

C3-C7 cycloalkyl substituted by R2, R3, R5, R6; provided R2 is not H;

CO₂H or R7; provided R8 is not H or unsubstituted alkyl;

NR8R8, NR7R8, NR7R7; provided R8 is not H or unsubstituted alkyl; and

SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8, provided R8 is not H ormethyl; and n is 1 or 2.

In the embodiments described above, Z′″ may be H and Z″ may be CH₂Cl,CH₂Br, CH₂I, CH₂OR, CH₂NH₂, CH₂N(R)₂, CH₂N(R)COR or CH₂N(R)CO₂R. R maybe H or C₁-C₆ alkyl.

In the embodiments described above, Z″ may be H and Z′″ may be selectedfrom the group consisting of H, C(R2)₂-halo, C(R2)₂R, C(R2)₂OR,C(R2)₂COR, C(R2)₂OCOR, C(R2)₂CO₂R, C(R2)₂N(R)₂, C(R2)₂SR, C(R2)₂SOR,C(R2)₂SO₂R, C(R2)₂N(R)CO_(n)R, C(R2)₂NRS(O)_(n)R, C(R2)₂NRC[═N(R)]N(R)₂,C(R2)₂N(R)N(R)CO_(n)R, C(R2)₂C(S)R, C(R2)₂C(S)N(R)₂, andC(R2)₂SO_(n)N(R)₂.

In specific embodiments, Z′″ may be selected from the group consistingof H, Me, CH2OH, CH2OAc, CH2OMe, CH2NHiPr, CH2NH2, CH2S(O)Bu, CH2S-iPr,CH2OCOtBu, CH2NHCH2CH2OMe, CH2NHCOiPr, CH2NHCOPh, CH2NHCO2Pr, CH2NHCOMe,CH2-4-Morpholino, CH2-1-piperidino, CH2NHBoc, CH2NHCO2Et, CH2NHCOEt,CH2NHS02iPr, CH2NHCbz, CH2NH(CH2)2-2-pyridyl, CH2NHCO-3-pyridyl,CH2NHCOCH2SCH2Ph, CH2NHCOCH2S(O)CH2Ph, CH2NHCO-2-furanyl,CH2N(CO2Et)CH2CH2OMe, NHCH(Me)CO2Et, CH2NHSO2Et, CH2NHSO2Me,CH2NMeSO2Me, CH2NMeTs, CH2NHCO2iPr, CH20COiPr, CH2-1-imidazole,CH2NHCH2CH2SEt, CH2N((CH2)2OMe)SO2Et, CH2NHCH2CF2CF3, CH2NHCH2CF2CF3,CH2NHCH2CF3, CH2NHCH2CH2OPh, CH2NHBu, CH2NHCH2Ph, CH2SCH2CF3,CH2NHCOCF3, CH2NHcyclopentyl, CH2NHCH2CH2NHBoc,CH2NH(CH2)3-1-pyrrolidine-2-one, CH2NHCH2cyclohexyl, CH2NHCH2-2-pyridyl,CH2NHCH2-4-(2-methylthiazole), CH2SO2Me, CH2NHCOCF2CF3, CH2OCH2CF3,CH2N(Ac)CH2CF3, and CH2NHCH2-5-benzofuranyl.

The inhibitor may be selected from the group of compounds in FIGS. 1-3.

The invention also provides a compound as described above, bound in acomplex with wild type or drug resistant mutant forms of HIV-1 protease.

The invention also provides a pharmaceutical composition comprising aneffective amount of an inhibitor as described above and apharmaceutically acceptable additive, excipient, or diluent. Thecomposition may also comprise another antiretroviral agent, such as asecond HIV inhibitor. The additional HIV inhibitor(s) may be an HIVprotease inhibitor and/or an HIV reverse transcriptase inhibitor.

The invention also provides a method of treating a patient sufferingfrom HIV infection, for example multi-drug resistant HIV infection,comprising administering to the patient a compound or composition asdescribed above. 25.A method of treatment according to claim 24 wherethe patient is suffering from a.

The invention further provides a method of inhibiting metabolicdegradation of a retroviral protease inhibitor in a subject beingtreated with the inhibitor, comprising administering to the subject adegradation-inhibiting amount of a compound as described above. Thecompound may be administered substantially contemporaneously with theinhibitor and/or prior to administration of the inhibitor.

The invention also provides HIV protease inhibitors having the structure

where each R2 may be the same or different, and R2 is H or C1-C6 alkyl;optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groups may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂,C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR;

or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo,NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R,N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

and where D′ is selected from the group consisting of alkyl, alkenyl,alkynyl, aryl, cycloalkyl and aralkyl, and is optionally substituted byalkyl, halo, nitro, cyano, CF₃, halo-C1-C6 alkyl, O-alkyl, or S-alkyl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the structures of a selection of benzofuran-containing HIVprotease inhibitors.

FIG. 2 shows the structures of benzisoxazole containing HIV proteaseinhibitors.

FIG. 3 shows the structures of indazole containing HIV proteaseinhibitors.

DETAILED DESCRIPTION

The invention provides novel ‘resistance-repellent’ retroviral proteaseinhibitors and compounds that inhibit metabolic degradation ofretroviral protease inhibitors. More specifically, the inventionprovides compounds that are active against a wide cross-section of HIVstrains. The invention further provides compounds that not only inhibitHIV protease, but that also inhibit one or more of the metabolic enzymesthat degrade protease inhibitors in vivo. These compounds may be usedfor treating HIV/AIDS either alone, or in combination with otheranti-HIV medicaments. In particular, the compounds that inhibitdegradation of protease inhibitors may be used either as a sole proteaseinhibitor or in combination with one or more different proteaseinhibitors to inhibit degradation of the other inhibitor(s) and therebymaintain intracellular concentrations of the protease inhibitor(s) at atherapeutic level for a sustained period of time. Advantageously,patients treated under such a regimen also receive therapeutic doses ofother anti-HIV medicaments such as reverse transcriptase inhibitors,cell fusion inhibitors and the like.

A ‘resistance-repellent’ protease inhibitor (“PI”) is a compound thatretains inhibitory activity, or potency, over a broad spectrum ofrelated but non-identical retroviral proteases. Examples ofresistance-repellent PIs include, but are not limited to, PIs thatinhibit wild type HIV-1 protease derived from any lade B virus and 1) awild type retroviral protease from one or more different retroviruses,such as HIV-2 protease; or 2) mutant HIV-1 proteases with single activesite mutations at residues 30, 82 and 84; or 3) mutant HIV-1 proteaseswith single active site mutations at residues 47, 48, and 50; or 4)mutant HIV-1 proteases with double active site mutations at residues 82and 84; or 5) mutant HIV-1 proteases with double active site mutationsat residues 47 and 48, 47 and 50, or 48 and 50; or 6) mutant HIV-1proteases with double active site mutations at residues 48 and 82, 48and 90, or 82 and 90; or 7) mutant HIV-1 proteases with three or moreactive site mutations in any combination at residues 32, 47, 48, 50, 82,84 or 90.

The term “pharmaceutically effective amount” refers to an amounteffective in treating a virus infection, for example an HIV infection,in a patient either as monotherapy or in combination with other agents.The term “treating” as used herein refers to the alleviation of symptomsof a particular disorder in a patient or the improvement of anascertainable measurement associated with a particular disorder. Theterm “prophylactically effective amount” refers to an amount effectivein preventing a virus infection, for example an HIV infection, in apatient. As used herein, the term “patient” refers to a mammal,including a human.

The applicants have found that compounds having the general formula Iare effective against a wide variety of PI-resistant HIV strainsX-A-B-A′-X′  I

where X is a moiety that contains two or more hydrogen bond acceptorscapable of interacting with the backbone NH atoms of residues 29 and 30of an HIV protease, A is a 2-6 atom linker that contains at least onehydrogen bond acceptor that interacts with the flap water, and onehydrogen bond donor that interacts with the backbone CO atom of residue27, B contains 1-3 atoms that can form hydrogen bonds with either orboth carboxylate side chain oxygens of Asp25 and Asp 125 of saidprotease, A′ is a 2-6 atom linker that contains at least one hydrogenbond acceptor that interacts with the flap water; and X′ is a moietythat can form one or more hydrogen bonds with the backbone NH atoms ofresidues 129 and/or 130. Some compounds conforming to this generalformula have been described and the present invention specificallyexcludes those compounds.

Resistance-repellent PIs should generally also retain inhibitoryactivity, or potency, over a broad spectrum of related but non-identicalretroviruses. In particular, resistance-repellent PIs should inhibit allHIV-1 virus strains that contain a gene sequence of the protease regionof the HIV-1 pol gene that is typified by one or more ‘wild type’strains derived from clade B and: 1) HIV-1 virus strains that contain agene sequence of the protease region of the HIV-1 pol gene derived fromwild type, non-clade B viruses; or 2) wild type HIV-2 virus strains; or3) HIV-1 virus strains derived from patients who are infected with HIV-1that contain mutations in the protease gene.

In a preferred embodiment, the instant invention provides an HIVprotease inhibitor represented by a formula:X-A-B-A′-X′

wherein,

X is a moiety that contains two or more hydrogen bond acceptors capableof interacting with the backbone NH atoms of residues 29 and 30 of saidprotease;

A is a 2-6 atom linker that contains at least one hydrogen bond acceptorthat interacts with the flap water, and one hydrogen bond donor thatinteracts with the backbone CO atom of residue 27 of said protease;

B contains 1-3 atoms that can form hydrogen bonds with either or bothcarboxylate side chain oxygens of Asp25 and Asp 125 of said protease;

A′ is a 2-6 atom linker that contains at least one hydrogen bondacceptor that interacts with a flap water of said protease;

X′ is a moiety that can form one or more hydrogen bonds with thebackbone NH atoms of residues 129 and/or 130 of said protease.Advantageously, X′ comprises a bicyclic moiety which is a substituted orunsubstituted substituted or unsubstituted benzofuran, benzofuranone,benzisoxazole, benzindazole, chroman-4-one, and indazole.

In a particular embodiment the invention provides an HIV proteaseinhibitor represented by the formula I:X-A-B-A′-X′  I

wherein X is a moiety that contains two or more hydrogen bond acceptorscapable of interacting with the backbone NH atoms of residues 29 and 30of an HIV protease;

A is a 2-6 atom linker that contains at least one hydrogen bond acceptorthat interacts with a flap water of said protease, and one hydrogen bonddonor that interacts with the backbone CO atom of residue 27 of saidprotease;

B contains 1-3 atoms that can form hydrogen bonds with either or bothcarboxylate side chain oxygens of Asp25 and Asp 125 of said protease;

A′ is a 2-6 atom linker that contains at least one hydrogen bondacceptor that interacts with the flap water of said protease; and

X′ is a moiety that can form one or more hydrogen bonds with thebackbone NH atoms of residues 129 and/or 130 of said protease.Advantageously, X′ comprises a bicyclic moiety which is a substituted orunsubstituted substituted or unsubstituted benzofuran, benzofuranone,benzisoxazole, benzindazole, chroman-4-one, and indazole.

In another embodiment, the invention provides an HIV protease inhibitorrepresented by a formula:X-A-B-A′-X′

wherein:

-   -   X is a 5-7 membered non-aromatic monocyclic heterocycle, wherein        said heterocycle is optionally fused or bridged with one or more        3-7 membered non-aromatic monocyclic heterocycle to form a        polycyclic system, wherein any of said heterocyclic ring systems        contains one or more heteroatoms selected from O, N, S, or P;        wherein any nitrogen forming part of the heterocycles may        optionally be substituted by R2, R3, R6, R7 or O; wherein any        sulfur may be optionally be substituted by one or two oxygen        atoms; wherein any P may be optionally be substituted by one or        more of O, NR2, or S, and any of said ring systems optionally        contains 1 to 6 substituents selected from the group consisting        of R2, R3, R5, and R6;    -   A is ZCZNH, ZCOCONH, ZS(O)₂NH, ZP(O)(V)NH, CONH, COCONH,        S(O)₂NH, P(O)(V)NH, wherein Z is NR2, O, S, or C(R2)₂, and V is        OR2 or NR2;    -   B is        wherein D is selected from alkyl, alkenyl, alkynyl, aryl,        cycloalkyl, or aralkyl optionally substituted with one or more        groups selected from alkyl, halo, nitro, cyano, CF₃, C3-C7        cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, NHR2, OR3, SR3,        NHR3, OR6, SR6, or NHR6;

A′ is N(D′)E′, wherein D′ is selected from alkyl, alkenyl, alkynyl,aryl, cycloalkyl, or aralkyl optionally substituted by alkyl, halo,nitro, cyano, CF₃, O-alkyl, or S-alkyl, and E′ is —CO— or —SO₂—;

-   -   X′ is selected from the group consisting of aryl and heteroaryl,        which are optionally substituted with one or more of the        following groups:        -   oxo, halo, OR3, OR6, OR7, OR2 provided R2 is not H or            unsubstituted alkyl;        -   alkyl optionally substituted by R3, R5, R6 provided R5 is            not halo;        -   C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8            cycloalkenyl, and heterocyclo, which groups may be            optionally substituted with one or more substituents            selected from R5;        -   aryl or heteroaryl, wherein said aryl or heteroaryl may be            optionally substituted with one or more groups selected from            the group consisting of aryl, heteroaryl, R2, R3, R4, and            R6;        -   C3-C7 cycloalkyl substituted by R2, R3, R5, R6; provided R2            is not H;        -   CO₂H or R7; provided R8 is not H or unsubstituted alkyl;        -   NR8R8, NR7R8, NR7R7; provided R8 is not H or unsubstituted            alkyl;        -   SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8, provided R8 is            not H or methyl;        -   and n is 1 or 2.    -   R is H or alkyl, aryl, alkenyl, alkynyl, cycloalkyl,        cycloalkenyl, heterocyclo, heterocycloalkyl, heteroaryl;        optionally substituted by halo, hydroxy, alkoxy, aryloxy,        cycloalkoxy, heteroaryloxy, cyano, nitro, alkylthio, arylthio,        cycloalkylthio, amino, or mono- or dialkylamino, mono- or        diarylamino, mono- or di-cycloalkylamino, mono- or        di-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl,        carboxamido, mono- or dialkylcarboxamido, mono- or        diarylcarboxamido, sulfonamido, mono- or dialkylsulfonamido,        mono- or diarylsulfonamido, alkylsulfinyl, alkylsulfonyl,        arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl,        cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;    -   R2 is H or C1-C6 alkyl; optionally substituted by C2-C6 alkenyl,        C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl,        heterocyclo; which groups may be optionally substituted with one        or more substituents selected from the group consisting of halo,        OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,        SO_(n)N(R)₂, SR, SONR, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,        NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR,        oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,        ═NNRS(O)_(n)N(R)₂, ═NNRS(O)_(n)(R), or wherein two R groups        together are —(CH₂)₄₋₆— optionally interrupted by one O, S, NH,        N-(aryl), N-(aryl(lower alkyl)), N-(carboxy(lower alkyl)) or        N-(optionally substituted C₁₋₂ alkyl) group;    -   or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which        groups may be optionally substituted with one or more        substituents selected from the group consisting of halo, OR,        ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,        SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,        NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;    -   or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH,        R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,        SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,        NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR,        oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCOnR,        ═NNRS(O)nN(R)₂, or ═NNRS(O)n(R);    -   R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8        cycloalkenyl, or heterocyclo; which groups may be optionally        substituted with one or more substituents selected from the        group consisting of halo, OR2, R2-OH, R2-halo, NO₂, CN,        CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,        S(O)nN(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2,        NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂,        NR2PO_(n)OR2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂,        ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, or ═NNR2S(O)_(n)(R2);    -   R4 is halo, OR8, R2-OH, R3-OH, R2-halo, R3-halo, NO₂, CN,        CO_(n)R8, CO_(n)R8, CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)R8,        C(S)N(R8)₂, SO_(n)N(R8)₂, SR8, SO_(n)R8, N(R8)₂, N(R8)CO_(n)R8,        NR8S(O)_(n)R8, NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)CO_(n)R8,        NR8PO_(n)N(R8)_(2,) NR8PO_(n)OR8, OC(O)R2, OC(S)R8, OC(O)N(R8)₂,        OC(S)N(R8)₂, OPO_(n)(R8)₂;    -   R5 is OR8, N(R8)₂, NHOH, N(R8)COR8, NR8S(O)_(n)R8,        NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)C(O)R8, NR8PO_(n)N(R8)₂,        NR8PO_(n)OR8, R2OH, R3-OH, R2-halo, R3-halo, CN, CO_(n)R8;        provided that when n=2, R8 is not H; CON(R8)₂, C(O)N(R8)N(R8)₂,        C(S)_(n)R8, C(S)N(R8)₂, S(O)_(n)R8, SO_(n)N(R8)₂, halo, NO₂,        SR8, oxo, ═N—OH, ═N—OR8, ═N—N(R8)₂, ═NR8, ═NNR8C(O)N(R8)₂,        ═NNR8C(O)_(n)R8, ═NNR8S(O)_(n)N(R8)₂, or ═NNR8S(O)_(n)(R8), or        R3    -   R6 is aryl or heteroaryl, wherein said aryl or heteroaryl may be        optionally substituted with one or more groups selected from        aryl, heteroaryl, R2, R3, halo, OR2, R2OH, R2-halo, NO₂, CN,        CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,        S(O)_(n)N(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2,        NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R,        NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,        OC(S)N(R2)₂, OPO_(n)(R2)₂    -   R7 is C(O)_(n)R8; provided that when n=2; R8 is not H; C(S)R8,        C(O)N(R8)₂, C(S)N(R8)₂, S(O)_(n)R8, S(O)nN(R8)₂;    -   R8 is R2, R3, or R6;

each n is independently 1 or 2;

its stereoisomeric forms; and

its pharmacologically acceptable salts.

In one variation, X is

Y is O, NH, or S;

z is O, NH, or S; and

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

In another variation, X is

wherein

G is C, O, NR2, or S;

n is an integer between 1-2; and

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

In another variation, X is

wherein

J is independently CH₂, or O, and

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

In yet another variation, X is

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

In another variation, X is

wherein each L is independently H, lower alkyl, oxo, or L forms acarbocyclic or heterocyclic ring with M;

-   -   each M is independently H, OH, chloro, fluoro, or M forms a        carbocyclic or heterocyclic ring with Q, provided that if one M        is OH, the other M is not OH;    -   Q is H, OH, amino, lower alkyl, alkylamino, alkoxy, halo, or        forms a 3-7-membered carbocyclic or heterocyclic ring together        with T;    -   each F is independently H, OH, lower alkyl, halo, or        spirocylopropyl, provided that if one R is OH, the other R is        not OH;    -   T is H or F, or T forms a carbocyclic or heterocyclic ring        together with F.

In another variation, X is tetrahydrofurodihydrofuranyl,tetrahydrofurotetrahydrofuranyl, tetrahydropyranotetrahydrofuranyl ortetrahydropyranodihydrofuranyl;

-   -   A is OCONH;    -   B is        wherein D is selected from alkyl, alkenyl, alkynyl, aryl,        cycloalkyl, or aralkyl optionally substituted with one or more        groups selected from alkyl, halo, nitro, cyano, CF₃, C3-C7        cycloalkyl, C5-C7 cycloalkenyl, R6, OR2, SR2, NHR2, OR3, SR3,        NHR3, OR6, SR6, or NHR6; and    -   A′ is N(D′)E′, wherein D′ is alkyl, alkenyl, alkynyl aryl,        cycloalkyl, or aralkyl optionally substituted by alkyl, halo, or        CF₃, and E′ is —SO₂—.

In another ariation, X is tetrahydrofurotetrahydrofuranyl;

A is OCONH;

B is

wherein D is benzyl; and

A′is N(D′)E′, wherein D′ is isobutyl and E′ is —SO₂—;

According to another variation, X is

wherein A2, B2, and C′ are each independently O, NR2, or S;

D2 is CH or N; and

n is an integer between 1 and 2.

According to another variation, X is

wherein

A3 is H, F or alkoxy;

B3 is F, alkoxy, lower alkyl, or A3 and B3 can form a 3-7 memberedheterocyclic ring;

Z′ is O, NR2, or S; and

n is an integer between 1-3.

In one embodiment, X′ is selected from the group that comprises

wherein said groups are optionally substituted with one or more of thefollowing groups:

-   -   oxo, halo, OR3, OR6, OR7, OR2 provided R2 is not H or        unsubstituted alkyl;    -   alkyl optionally substituted by R3, R5, R6 provided R5 is not        halo;    -   C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8        cycloalkenyl, and heterocyclo, which groups may be optionally        substituted with one or more substituents selected from R5;    -   aryl or heteroaryl, wherein said aryl or heteroaryl may be        optionally substituted with one or more groups selected from the        group consisting of aryl, heteroaryl, R2, R3, R4, and R6;    -   C3-C7 cycloalkyl substituted by R2, R3, R5, R6; provided R2 is        not H;    -   CO₂H or R7; provided R8 is not H or unsubstituted alkyl;    -   NR8R8, NR7R8, NR7R7; provided R8 is not H or unsubstituted        alkyl; and    -   SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8, provided R8 is not H        or methyl;    -   and n is 1 or2.

In another embodiment, X′ is selected from

wherein

G′ and R′ cannot both be H;

G′ and R′ are each independently:

-   -   H or alkyl substituted by R3, R5, R6 provided R5 is not halo;    -   C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8        cycloalkenyl, and heterocyclo, which groups may be optionally        substituted with one or more substituents selected from the        group consisting of —OR2, C(O)N(R2)₂, S(O)_(n)N(R2)₂, CN, SR2,        SO_(n)R2, COR2, CO₂R2 or NR2C(O)R2, R5, and R7;    -   aryl or heteroaryl, wherein said aryl or heteroaryl may be        optionally substituted with one or more groups selected from the        group consisting of aryl, heteroaryl, R2, R3, R4, and R6;    -   C3-C7 cycloalkyl substituted by R2, R3, R5, R6; provided R2 is        not H;    -   CO₂H or R7 provided R2 is not H or unsubstituted alkyl; and    -   SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8, provided R8 is not H        or methyl; and n is 1 or 2.

Particular compounds are selected from the group of compounds in FIGS. 1to 3.

In another variation, preferably, X is

wherein A2, B2, and C are each independently O, NR2, or S;

D2 is CH or N; and

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

Preferably, X is

wherein

A3 is H, F or alkoxy;

B3 is F, alkoxy, lower alkyl, or A and B can form a 3-7 memberedheterocyclic ring;

z is O, NR2, or S;

n is an integer between 1-3; and

wherein any ring carbon is optionally substituted by R2, R3, R5, R6.

With regard to X, X may also be a 5-7 membered non-aromatic monocyclicheterocycle, wherein said heterocycle is optionally fused or bridgedwith one or more 3-7 membered non-aromatic monocyclic heterocycle toform a polycyclic system, wherein any of said heterocyclic ring systemscontains one or more heteroatoms selected from O, N, S, or P; whereinany nitrogen forming part of the heterocycles may optionally besubstituted by R2, R3, R6, R7 or O; wherein any sulfur may be optionallybe substituted by one or two oxygen atoms; wherein any P may beoptionally be substituted by one or more of O NR2, or S, and any of saidring systems optionally contains 1 to 6 substituents selected from thegroup consisting of R2, R3, R5, and R6.

X may also be

wherein, Y is O, NH, or S; Z is O, NH, or S; and wherein any ring carbonis optionally substituted by R2, R3, R5, or R6.

X may also be

wherein G is C, O, NR2, or S; n is an integer between 1-2; and whereinany ring carbon is optionally substituted by R2, R3, R5, or R6.

X may also be

wherein J is independently CH₂, or O and wherein any ring carbon isoptionally substituted by R2, R3, R5, or R6.

X may also be

wherein any ring carbon is optionally substituted by R2, R3, R5, or R6.

X may also be

wherein each L is independently H, lower alkyl, oxo, or L forms acarbocyclic or heterocyclic ring with M; each M is independently H, OH,chloro, fluoro, or M forms a carbocyclic or heterocyclic ring with Q,provided that if one M is OH, the other M is not OH; Q is H, OH, amino,lower alkyl, alkylamino, alkoxy, halo, or forms a 3-7-memberedcarbocyclic or heterocyclic ring together with T; each F isindependently H, OH, lower alkyl, halo, or spirocylopropyl, providedthat if one R is OH, the other R is not OH; T is H or F, or T forms acarbocyclic or heterocyclic ring together with F.

X may also be

wherein A2, B2, and C′ are each independently O, NR2, or S; D2 is CH orN; and n is an integer between 1 and 2.

X may also be

wherein A3 is H, F or alkoxy; B3 is F, alkoxy, lower alkyl, or A3 and B3can form a 3-7 membered heterocyclic ring; Z′ is O, NR2, or S; and n isan integer between 1-3.

X is preferably tetrahydrofurodihydrofuranyl,tetrahydrofuro-tetrahydrofuranyl, tetrahydropyrano-tetrahydrofuranyl ortetrahydropyranodihydrofuranyl. More preferably, X istetrahydrofurotetrahydro-furanyl.

With regard to A, A may be ZCZNH, ZCOCONH, ZS(O)₂NH, ZP(O)(V)NH, CONH,COCONH, S(O)₂NH, P(O)(V)NH, wherein Z is NR2, O, S, or C(R2)₂, and V isOR2 or NR2. A is preferably OCONH.

With regard to B, B may be

wherein D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oraralkyl optionally substituted with one or more groups selected fromalkyl, halo, nitro, cyano, CF₃, C3-C7 cycloalkyl, C5-C7 cycloalkenyl,R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6.

With regard to A′, A′ may be N(D′)E′, wherein D′ is selected from alkyl,alkenyl, alkynyl, aryl, cycloalkyl, or aralkyl optionally substituted byalkyl, halo, nitro, cyano, CF₃, O-alkyl, or S-alkyl, and E′ is —CO— or—SO₂—. Preferably, D′ is alkyl, alkenyl, alkynyl aryl, cycloalkyl, oraralkyl optionally substituted by alkyl, halo, or CF₃, and E′ is —SO₂—.More preferably, D′ is isobutyl and E′ is —SO₂—.

With regard to X′, X′ is selected from the group consisting of asubstituted or unsubstituted benzofuran, benzofuranone, benzisoxazole,benzindazole, chroman-4-one, and indazole. When substituted, X′ may besubstituted with -Me, —CH₂NH₂, —CH₂NHCOMe, —CH₂-morpholine,—CH₂-piperidine, —CH₂NHBoc, —CH₂SO-Bu, —CH₂NHCO₂Et, —CH₂NHCOPh,—CH₂NHCBz, —CH₂NH(CH₂)₂-2-pyridine, —NH₂, —CH₂NH-ipropyl,—CH₂NHSO₂-i-propyl, —CH₂OAc, —CH₂CH(Me)CO₂Et, —CH₂NSO₂Me, —CH₂SOBu,—CH₂S-i-propyl, —CH₂NMeSO₂Me, —CH₂NMeTs, —NH(2-butyl), —NH(2-amyl),—NH-cyclohexyl, —NH-propyl, —NHCH₂Ph, —NH-3-amyl, —NH-butyl, and—NHCH₂-t-butyl.

Further, when substituted, X′ may be substituted with aryl andheteroaryl, which are substituted with one or more of the followinggroups: OR3, OR6, OR7, OR2 provided R2 is not H or unsubstituted alkyl;alkyl substituted by R3, R5, R6 provided R5 is not halo; C2-C6 alkenyl,C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and heterocyclo,which groups may be optionally substituted with one or more substituentsselected from R5; aryl or heteroaryl, wherein said aryl or heteroarylmay be optionally substituted with one or more groups selected from thegroup consisting of aryl, heteroaryl, R2, R3, R4, and R6; C3-C7cycloalkyl substituted by R2, R3, R5, R6; provided R2 is not H; CO₂H orR7; provided R8 is not H or unsubstituted alkyl; NR8R8, NR7R8, NR7R7;provided R8 is not H or unsubstituted alkyl; SO_(n)N(R8)₂, SO_(n)NR7R8,SR8, S(O)_(n)R8, provided R8 is not H or methyl; and n is 1 or 2.

Preferably, R is H or alkyl, aryl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, heteroaryl; optionally substituted by halo,hydroxy, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, cyano, nitro,alkylthio, arylthio, cycloalkylthio, amino, or mono- or dialkylamino,mono- or diarylamino, mono- or di-cycloalkylamino, mono- ordi-heteroarylamino, alkanoyl, cycloalkanoyl, aroyl, heteroaroyl,carboxamido, mono- or dialkylcarboxamido, mono- or diarylcarboxamido,sulfonamido, mono- or dialkylsulfonamido, mono- or diarylsulfonamido,alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl,cycloalkylsulfinyl, cycloalkylsulfonyl, heteroarylsulfinyl,heteroarylsulfonyl.

Prererably, R2 is H or C1-C6 alkyl; optionally substituted by C2-C6alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl,heterocyclo; which groups may be optionally substituted with one or moresubstituents selected from the group consisting of halo, OR, ROH,R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR,SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R); or R2is C1-C6 alkyl; substituted by aryl or heteroaryl; which groups may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂,C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR; or R2 is C1-C6 alkyl; optionally substituted by halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR,═NNRC(O)N(R)₂, ═NNRCOnR, ═NNRS(O)nN(R)₂, or ═NNRS(O)n(R).

Preferably, R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8cycloalkenyl, or heterocyclo; which groups may be optionally substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)nN(R2)₂, SR2, SO_(n)R2, N(R)₂,N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2,NR2PO_(n)N(R2)_(2,) NR2PO_(n)OR2, oxo, ═N—OR2, ═N—N(R2)₂, ═NR2,═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂, or═NNR2S(O)_(n)(R2).

Preferably, R4 is halo, OR8, R2-OH, R3-OH, R2-halo, R3-halo, NO₂, CN,CO_(n)R8, CO_(n)R8, CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)R8, C(S)N(R8)₂,SOnN(R8)₂, SR8, SO_(n)R8, N(R8)₂, N(R8)CO_(n)R8, NR8 S(O)_(n)R8,NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)CO_(n)R8, NR8PO_(n)N(R8)₂, NR8PO_(n)OR8,OC(O)R2, OC(S)R8, OC(O)N(R8)₂, OC(S)N(R8)₂, OPO_(n)(R8)₂.

Preferably, R5 is OR8, N(R8)₂, NHOH, N(R8)COR8, NR8S(O)_(n)R8,NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)C(O)R8, NR8PO_(n)N(R8)₂, NR8PO_(n)OR8,R2OH, R3-OH, R2-halo, R3-halo, CN, CO_(n)R8; provided that when n=2, R8is not H; CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)_(n)R8, C(S)N(R8)₂, S(O)_(n)R8,SO_(n)N(R8)₂, halo, NO₂, SR8, oxo, ═N—OH, ═N—OR8, ═N—N(R8)₂, ═NR8,═NNR8C(O)N(R8)₂, ═NNR8C(O)_(n)R8, ═NNR8S(O)_(n)N(R8)₂, or═NNR8S(O)_(n)(R8), or R3.

Preferably, R6 is aryl or heteroaryl, wherein said aryl or heteroarylmay be optionally substituted with one or more groups selected fromaryl, heteroaryl, R2, R3, halo, OR2, R20H, R2-halo, NO₂, CN, CO_(n)R2,C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2,SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, OC(S)N(R2)₂, OPO_(n)(R2)₂.

Preferably, R7 is C(O)_(n)R8; provided that when n=2; R8 is not H;C(S)R8, C(O)N(R8)₂, C(S)N(R8)₂, S(O)_(n)R8, S(O)nN(R8)₂.

Preferably, R8 is R2, R3, or R6; and Z is N, O, or S.

In another embodiment, the invention also provides compounds of theinstant invention bound in a complex with wild type or drug resistantmutant forms of HIV-1 protease.

In still another embodiment, the invention also provides a compositioncomprising an inhibitor according to the instant invention and apharmaceutically acceptable additive, excipient, or diluent.

In yet another embodiment, the invention also provides an pharmaceuticalcomposition comprising an inhibitor according to the instant inventionand another antiretroviral agent.

In a further embodiment, the invention also provides a compositioncomprising an inhibitor according to the instant invention and a secondHIV inhibitor;

In a still further embodiment, the invention also provides an inhibitoraccording to the instant invention and an additional HIV proteaseinhibitor.

In yet another embodiment, the invention also provides an inhibitoraccording to the instant invention and an HIV reverse transcriptaseinhibitor.

In still another embodiment, the invention also provides a method oftreating a patient suffering from HIV infection, comprisingadministering to the patient one or more compounds and/or a compositionaccording to the instant invention. The patient may suffer from amulti-drug resistant HIV infection.

In another embodiment, there is provided a method of inhibitingmetabolic degradation of a retroviral protease inhibitor in a subjectbeing treated with said inhibitor, comprising administering to saidsubject a degradation-inhibiting amount of a compound according to theabove embodiments and variations.

In other embodiments,

X′ is

where G1 is NH or O;

where G2 is CZ″ or N;

where Z″ is selected from the group consisting of halogen, R2, R3, orR6;

where Z′″ is selected from the group consisting of H or R2, R3, R6,halo, haloalkyl, C(R2)₂OR, C(R2)₂COR, C(R2)₂OCOR, C(R2)₂CO₂R,C(R2)₂N(R)₂, C(R2)₂SR, C(R2)₂SOR, C(R2)₂SO₂R, optionally substitutedwith one or more substituents selected from the group consisting ofhalo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂,SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R,NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR;

where X′ is optionally substituted with one or more substituents, eachindependently selected from (a)-(h) as follows:

(a) OR3, OR6, OR7, OR2;

(b) alkyl substituted by R3, R5, R6;

(c) C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl,and heterocyclyl, which groups may be optionally substituted with one ormore substituents selected from R5;

(d) aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, R4 and R6;

(e) C3-C7 cycloalkyl substituted by R2, R3, R5 or R6;

(f) CO₂H or R7;

(g) NR8R8, NR7R8, NR7R7; and

(h) SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8; and n is 1 or 2;

R is H or is selected from the group consisting of alkyl, aryl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and heteroaryl;optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy,heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino,or mono- or dialkylamino, mono- or diarylamino, mono- ordi-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl,cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono- ordialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- ordialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl;

R2 is H or C1-C6 alkyl; optionally substituted by C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR;

or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo,NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R,N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

R3 is C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8cycloalkenyl, or heterocyclo; which groups may be optionally substitutedwith one or more substituents selected from the group consisting ofhalo, OR2, R2-OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, oxo, ═N—OR2,═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2, ═NNR2S(O)_(n)N(R2)₂,or ═NNR2S(O)_(n)(R2);

R4 is selected from the group consisiting of halo, OR8, R2-OH, R3-OH,R2-halo, R3-halo, NO₂, CN, CO_(n)R8, CO_(n)R8, CON(R8)₂,C(O)N(R8)N(R8)₂, C(S)R8, C(S)N(R8)₂, SO₁N(R8)₂, SR8, SO_(n)R8, N(R8)₂,N(R8)CO_(n)R8, NR8S(O)_(n)R8, NR8C[═N(R8)₂, N(R8)N(R8)CO_(n)R8,NR8PO_(n)N(R8)₂, NR8PO_(n)OR8, OC(O)R2, OC(S)R8, OC(O)N(R8)₂,OC(S)N(R8)₂ and OPO_(n)(R8)₂;

R5 is selected from the group consisting of OR8, N(R8)₂, NHOH,N(R8)COR8, NR8S(O)_(n)R8, NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)C(O)R8,NR8PO_(n)N(R8)₂, NR8PO_(n)OR8, R2OH, R3-OH, R2-halo, R3-halo, CN,CO_(n)R8; CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)_(n)R8, C(S)N(R8)₂, S(O)_(n)R8,SO_(n)N(R8)₂, halo, NO₂, SR8, oxo, ═N—OH, ═N—OR8, ═N—N(R8)₂, ═NR8,═NNR8C(O)N(R8)₂, ═NNR8C(O)_(n)R8, ═NNR8S(O)_(n)N(R8)₂, or═NNR8S(O)_(n)(R8) and R3;

R6 is aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from aryl, heteroaryl, R2,R3, halo, OR2, R2OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SR2, SO_(n)R2,N(R)₂, N(R2)CO_(n)R, NRS(O)_(n)R2, NR2C[═N(R2)]N(R2)₂,N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, OC(O)R2, OC(S)R2,OC(O)N(R2)₂, OC(S)N(R2)₂, OPO_(n)(R2)₂;

R7 is selected from the group consisting of C(O)_(n)R8; C(S)R8,C(O)N(R8)₂, C(S)N(R8)₂, S(O)_(n)R8 and S(O)nN(R8)₂;

R8 is R2, R3, or R6;

R9 is alkyl optionally substituted by R3, R5, R6; C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, and heterocyclo, whichgroups may be optionally substituted with one or more substituentsselected from the group consisting of —OR2, C(O)N(R2)₂, S(O)_(n)N(R2)₂,CN, SR2, SO_(n)R2, COR2, CO₂R2 or NR2C(O)R2, R5, and R7; aryl orheteroaryl, where the aryl or heteroaryl may be optionally substitutedwith one or more groups selected from the group consisting of aryl,heteroaryl, R2, R3, R4, and R6; C3-C7 cycloalkyl optionally substitutedby R2, R3, R5, R6; CO₂H or R7; NR3R3, NR6R6, NR7R7, NR3R6, NR6R7, NR3R7,NR2R3, NR2R6, NR2R7, NR2R2; SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8;and n is 1 or 2; SO_(n)N(R2)₂, SO_(n)N(R3)₂, SO_(n)N(R6)₂, SO_(n)N(R7)₂,SO_(n)NR2R3, SO_(n)NR2R6, SO_(n)NR2R7, SO_(n)NR3R6, SO_(n)NR3R7,SO_(n)NR6R7; S(O)_(m)R2, S(O)_(m)R3, S(O)_(m)R6; and m is 0, 1 or 2; andeach n is independently 1 or 2.

In other embodiments, X′ is selected from

where the groups are optionally substituted with one or more of thefollowing groups:

oxo, halo, OR3, OR6, OR7, OR2 provided R2 is not H or unsubstitutedalkyl;

alkyl optionally substituted by R3, R5, R6 provided R5 is not halo;

C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, andheterocyclo, which groups may be optionally substituted with one or moresubstituents selected from R5;

aryl or heteroaryl, where the aryl or heteroaryl may be optionallysubstituted with one or more groups selected from the group consistingof aryl, heteroaryl, R2, R3, R4, and R6;

C3-C7 cycloalkyl substituted by R2, R3, R5, R6; provided 2 is not H;

CO₂H or R7; provided R8 is not H or unsubstituted alkyl;

NR8R8, NR7R8, NR7R7; provided R8 is not H or unsubstituted alkyl; and

SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8, provided R8 is not H ormethyl; and n is 1 or 2.

In the embodiments described above, Z′″ may be H and Z″ may be CH₂Cl,CH₂Br, CH₂I, CH₂OR, CH₂NH₂, CH₂N(R)₂, CH₂N(R)COR or CH₂N(R)CO₂R. R maybe H or C₁-C₆ alkyl.

In the embodiments described above, Z″ may be H and Z′″ may be selectedfrom the group consisting of H, C(R2)₂-halo, C(R2)₂R, C(R2)₂OR,C(R2)₂COR, C(R2)₂OCOR, C(R2)₂CO₂R, C(R2)₂N(R)₂, C(R2)₂SR, C(R2)₂SOR,C(R2)₂SO₂R, C(R2)₂N(R)CO_(n)R, C(R2)₂NRS(O)_(n)R, C(R2)₂NRC[═N(R)]N(R)₂,C(R2)₂N(R)N(R)CO_(n)R, C(R2)₂C(S)R, C(R2)₂C(S)N(R)₂, andC(R2)₂SO_(n)N(R)₂. In specific embodiments, Z′″ may be selected from thegroup consisting of H, Me, CH2OH, CH2OAc, CH2OMe, CH2NHiPr, CH2NH2,CH2S(O)Bu, CH2S-iPr, CH2OCOtBu, CH2NHCH2CH2OMe, CH2NHCOiPr, CH2NHCOPh,CH2NHCO2Pr, CH2NHCOMe, CH2-4-Morpholino, CH2-1 -piperidino, CH2NHBoc,CH2NHCO2Et, CH2NHCOEt, CH2NHSO2iPr, CH2NHCbz, CH2NH(CH2)2-2-pyridyl,CH2NHCO-3-pyridyl, CH2NHCOCH2SCH2Ph, CH2NHCOCH2S(O)CH2Ph,CH2NHCO-2-furanyl, CH2N(CO2Et)CH2CH2OMe, NHCH(Me)CO2Et, CH2NHSO2Et,CH2NHSO2Me, CH2NMeSO2Me, CH2NMeTs, CH2NHCO2iPr, CH2OCOiPr,CH2-1-imidazole, CH2NHCH2CH2SEt, CH2N((CH2)2OMe)SO2Et, CH2NHCH2CF2CF3,CH2NHCH2CF3, CH2NHCH2CH2OPh, CH2NHBu, CH2NHCH2Ph, CH2SCH2CF3,CH2NHCOCF3, CH2NHcyclopentyl, CH2NHCH2CH2NHBoc,CH2NH(CH2)3-1-pyrrolidine-2-one, CH2NHCH2cyclohexyl, CH2NHCH2-2-pyridyl,CH2NHCH2-4-(2-methylthiazole), CH2SO2Me, CH2NHCOCF2CF3, CH2OCH2CF3,CH2N(Ac)CH2CF3, and CH2NHCH2-5-benzofuranyl.

The inhibitor may be selected from the group of compounds in FIGS. 1-3.

The invention also provides a compound as described above, bound in acomplex with wild type or drug resistant mutant forms of HIV-1 protease.

The invention also provides a pharmaceutical composition comprising aneffective amount of an inhibitor as described above and apharmaceutically acceptable additive, excipient, or diluent. Thecomposition may also comprise another antiretroviral agent, such as asecond HIV inhibitor. The additional HIV inhibitor(s) may be an HIVprotease inhibitor and/or an HIV reverse transcriptase inhibitor.

The invention also provides a method of treating a patient sufferingfrom HIV infection, for example multi-drug resistant HIV infection,comprising administering to the patient a compound or composition asdescribed above. 25.A method of treatment according to claim 24 wherethe patient is suffering from a.

The invention further provides a method of inhibiting metabolicdegradation of a retroviral protease inhibitor in a subject beingtreated with the inhibitor, comprising administering to the subject adegradation-inhibiting amount of a compound as described above. Thecompound may be administered substantially contemporaneously with theinhibitor and/or prior to administration of the inhibitor.

The invention also provides HIV protease inhibitors having the structure

where each R2 may be the same or different, and R2 is H or C1 -C6 alkyl;optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groups may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂,C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(N)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R);

or R2 is C1-C6 alkyl; substituted by aryl or heteroaryl; which groupsmay be optionally substituted with one or more substituents selectedfrom the group consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR;

or R2 is C1-C6 alkyl; optionally substituted by halo, OR, ROH, R-halo,NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R,N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R,NRPO_(n)N(R)₂, NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂,═NNRCO_(n)R, ═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R); and where D′ isselected from the group consisting of alkyl, alkenyl, alkynyl, aryl,cycloalkyl and aralkyl, and is optionally substituted by alkyl, halo,nitro, cyano, CF₃, halo-C1-C6 alkyl, O-alkyl, or S-alkyl.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, solvates, hydrates, tautomers orprodrugs thereof. Such derivatives may be readily prepared by those ofskill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine, 1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethyl-benzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, nitrates, borates, methanesulfonates, benzenesulfonates,toluenesulfonates, salts of mineral acids, such as but not limited tohydrochlorides, hydrobromides, hydroiodides and sulfates; and salts oforganic acids, such as but not limited to acetates, trifluoroacetates,maleates, oxalates, lactates, malates, tartrates, citrates, benzoates,salicylates, ascorbates, succinates, butyrates, valerates and fumarates.Pharmaceutically acceptable esters include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl,cycloalkyl and heterocyclyl esters of acidic groups, including, but notlimited to, carboxylic acids, phosphoric acids, phosphinic acids,sulfonic acids, sulfinic acids and boronic acids. Pharmaceuticallyacceptable enol ethers include, but are not limited to, derivatives offormula C═C(OR) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl or heterocyclyl.Pharmaceutically acceptable enol esters include, but are not limited to,derivatives of formula C═C(OC(O)R) where R is hydrogen, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl orheterocyclyl. Pharmaceutically acceptable solvates and hydrates arecomplexes of a compound with one or more solvent or water molecules, or1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent orwater molecules.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized by one or more steps or processes orotherwise converted to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, thepharmaceutically active compound is modified such that the activecompound will be regenerated by metabolic processes. The prodrug may bedesigned to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound (see,e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388-392). As used herein, prodrugsinclude phosphonates.

Also included in the present application are one or more of the variouspolymorphs of the compounds. A crystalline compound disclosed in thepresent application may have a single or may have multiple polymorphs,and these polymorphs are intended to be included as compounds of thepresent application. Also, where a single polymorph is noted, thepolymorph may change or interconvert to one or more differentpolymorphs, and such polymorph or polymorph mixtures are included in thepresent application.

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues may be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified the residue is the L form. As used herein, the term “aminoacid” refers to a-amino acids which are racemic or of either the D- orL-configuration. The designation “d” preceding an amino acid designation(e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.The designation “d1” preceding an amino acid designation (e.g., dlPip)refers to a mixture of the L- and D-isomers of the amino acid. It is tobe understood that the chiral centers of the compounds provided hereinmay undergo epimerization in vivo. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form.

It is also to be understood that the compounds provided herein may havetautomeric forms. All such tautomeric forms are included within thescope of the instant disclosure. For example, a 3-enamino-2-oxindolewhere the amino group of the enamine has a hydrogen substituent has thetautomeric form of a 3-imino-2-hydroxyindole.

The term “alkyl”, alone or in combination with any other term, refers toa straight-chain or branch-chain saturated aliphatic hydrocarbon radicalcontaining the specified number of carbon atoms, or where no number isspecified, preferably from 1 to about 15 and more preferably from 1 toabout 10 carbon atoms. Examples of alkyl radicals include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isoamyl, n-hexyl and the like.

The term “alkenyl”, alone or in combination with any other term, refersto a straight-chain or branched-chain mono- or poly-unsaturatedaliphatic hydrocarbon radical containing the specified number of carbonatoms, or where no number is specified, preferably from 2-10 carbonatoms and more preferably, from 2-6 carbon atoms. Examples of alkenylradicals include, but are not limited to, ethenyl, E- and Z-propenyl,isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl,E- and Z-hexenyl, E,E-, E,Z-, Z,E- and Z,Z-hexadienyl and the like.

The term “alkynyl,” alone or in combination with any other term, refersto a straight-chain or branched-chain hydrocarbon radical having one ormore triple bonds containing the specified number of carbon atoms, orwhere no number is specified, preferably from 2 to about 10 carbonatoms. Examples of alkynyl radicals include, but are not limited to,ethynyl, propynyl, propargyl, butynyl, pentynyl and the like.

The term “alkoxy” refers to an alkyl ether radical, wherein the term“alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term “aryl,” alone or in combination with any other term, refers toa carbocyclic aromatic radical (such as phenyl or naphthyl) containingthe specified number of carbon atoms, preferably from 6-15 carbon atoms,and more preferably from 6-10 carbon atoms, optionally substituted withone or more substituents selected from alkyl, alkoxy, (for examplemethoxy), nitro, halogen, (for example chloro), amino, carboxylate andhydroxy. Examples of aryl radicals include, but are not limited tophenyl, p-tolyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, indenyl,indanyl, azulenyl, fluorenyl, anthracenyl and the like.

The term “aralkyl”, alone or in combination, means an alkyl radical asdefined above in which one hydrogen atom is phenyl, benzyl,2-phenylethyl and the like.

The term “aralkoxy carbonyl”, alone or in combination, means a radicalof the formula —C(O)—O-aralkyl in which the term “aralkyl” has thesignificance given above. An example of an aralkoxycarbonyl radical isbenzyloxycarbonyl.

The term “aryloxy”, alone or in combination, means a radical of theformula aryl-O— in which the term “aryl” has the significance givenabove.

The term “alkanoyl”, alone or in combination, means an acyl radicalderived from an alkanecarboxylic acid, examples of which include acetyl,propionyl, butyryl, valeryl, 4-methylvaleryl, and the like.

The term “aryloxyalkanoyl” means an acyl radical of the formulaaryl-O-alkanoyl wherein aryl and alkanoyl have the significance givenabove.

The term “aralkanoyl” means an acyl radical derived from anaryl-substituted alkanecarboxylic acid such as phenylacetyl,3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl,4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-phenylbutyryl,(1-naphthyl)acetyl, 4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl,4-methoxyhydrocinnamoyl, and the like.

The term “aroyl” means an acyl radical derived from an aromaticcarboxylic acid. Examples of such radicals include aromatic carboxylicacids, an optionally substituted benzoic or naphthoic acid such asbenzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-benzyloxycarbonyl)benzoyl,1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl,6-(benzyloxycarbonyl)-2-naphthoyl, 3-benzyloxy-2-naphthoyl,3-hydroxy-2-naphthoyl, 3-(benzyloxyformamido)-2-naphthoyl, and the like.

The term “aminocarbonyl” alone or in combination, means anamino-substituted carbonyl(carbamoyl) group derived from anamino-substituted carboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group continuing substituentsselected from hydrogen, alkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl radicals and the like.

The term “aminoalkanoyl” means an acyl radical derived from an aminosubstituted alkanecarboxylic acid wherein the amino group can be aprimary, secondary or tertiary amino group containing substituentsselected from the group consisting of hydrogen, cycloalkyl,cycloalkylalkyl radicals and the like, examples of which includeN,N-dimethylaminoacetyl and N-benzylaminoacetyl.

The term “carbocycle” refers to a non-aromatic stable 3- to 8-memberedcarbon ring which may be saturated, mono-unsaturated orpoly-unsaturated. The carbocycle may be attached at any endocycliccarbon atom which results in a stable structure. Preferred carbocycleshave 5-7 carbons.

The term “cycloalkyl”, alone or in combination, means an alkyl radicalwhich contains from about 3 to about 8 carbon atoms and is cyclic.Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

The term “cycloalkylalkyl” means an alkyl radical as defined above whichis substituted by a cycloalkyl radical containing from about 3 to about8, preferably from about 3 to about 6, carbon atoms.

The term “cycloalkylcarbonyl” means an acyl group derived from amonocyclic or bridged cycloalkanecarboxylic acid such ascyclopropanecarbonyl, cyclohexanecarbonyl, adamantanecarbonyl, and thelike, or from a benz-fused monocyclic cycloalkanecarboxylic acid whichis optionally substituted by, for example, alkanoylamino, such as1,2,3,4-tetrahydro-2-naphthoyl,2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl.

The term “cycloalkylalkoxycarbonyl” means an acyl group derived from acycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O—COOHwherein cycloalkylalkyl has the significance given above.

The term “heterocyclyl” or “heterocycle” refers to a stable 3-7 memberedmonocyclic heterocyclic ring or 8-11 membered bicyclic heterocyclic ringwhich is either saturated or partially unsaturated, and which may beoptionally benzofused if monocyclic and which is optionally substitutedon one or more carbon atoms by halogen alkyl, alkoxy, oxo, and the like,and/or on a secondary nitrogen atom (i.e., —NH—) by alkyl,aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl or on a tertiarynitrogen atom (i.e., +N—) by oxido and which is attached via a carbonatom. Each heterocycle consists of one or more carbon atoms and from oneto four heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur. As used herein, the terms “nitrogen and sulfurheteroatoms” include any oxidized form of nitrogen and sulfur, and thequaternized form of any basic nitrogen. A heterocyclyl radical may beattached at any endocyclic carbon or heteroatom which results in thecreation of a stable structure. Preferred heterocycles include 5-7membered monocyclic heterocycles and 8-10 membered bicyclicheterocycles. Examples of such groups imidazolinoyl, imidazolidinyl,indazolinolyl, perhydropyridazyl, pyrrolinyl, pyrrolidinyl, piperidinyl,pyrazolinyl, piperazinyl, morpholinyl, thiamorpholinyl, thiazolidinyl,thiamorpholinyl sulfone, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl,tetrahydropyranyl, tetrahydrofuranyl, dioxolyl, dioxinyl, benzodioxolyl,dithiolyl, tetrahydrothienyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

The term heteroaryl refers to a stable 5-6 membered monocyclic or 8-11membered bicyclic aromatic heterocycles where heterocycles is as definedabove. Non-limiting examples of such groups include imidazolyl,quinolyl, isoquinolyl, indolyl, indazolyl, pyridazyl, pyridyl, pyrrolyl,pyrazolyl, pyrazinyl, quinoxolyl, pyranyl, pyrimidinyl, furyl, thienyl,triazolyl, thiazolyl, carbolinyl, tetrazolyl, benzofuranoyl,thiamorpholinyl sulfone, oxazolyl, benzoxazolyl, benzimidazolyl,benzthiazolyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl,isoxazolyl, isothiazolyl, furazanyl, thiazolyl, thiadiazolyl,oxathiolyl.

The term “heterocyclylalkanoyl” is an acyl radical derived from aheterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl hasthe significance given above.

The term “heterocyclyloxycarbonyl” means an acyl group derived fromheterocyclyl-O—COOH wherein heterocyclyl is as defined above.

The term “heterocyclylalkoxycarbonyl” means an acyl radical derived fromheterocyclyl-substituted alkane-O—COOH wherein heterocyclyl has thesignificance given above.

The term “heteroaryloxycarbonyl” means an acyl radical derived from acarboxylic acid represented by heteroaryl-O—COOH wherein heteroaryl hasthe significance given above.

The term “halogen” means fluorine, chlorine, bromine or iodine.

The term haloalkyl means an alkyl with one or more of its hydrogensreplaced by halogens. Haloalkyl also include perhaloalkyl groups orpartially halogenated alkyl groups, including for example, halo-C1-C6alkyl groups. Non-exclusive examples of haloalkyls include —CF3,—CF2CF3, —CH2CF3, and the like.

The term “thioalkyl” means an alkyl radical having at least one sulfuratom, wherein alkyl has the significance given above. An example of athioalkyl is CH₃SCH₃. The corresponding sulfoxide and sulfone of thisthioalkyl CH₃S(O)CH₃ and CH₃S(O)₂CH₃ respectively. Unless expresslystated to the contrary, the terms “—SO₂—” and “—S(O)₂—” as used hereinrefer to a sulfone or sulfone derivative (i.e., both appended groupslinked to the S), and not a sulfinate ester.

The term “substituted”, whether preceded by the term “optionally” ornot, and substitutions contained in formulas of this invention, refer tothe replacement of one or more hydrogen radicals in a given structurewith the radical of a specified substituent. Examples of substituentsinclude, but are not limited to, aldehydes, aliphatic, (C1-10)alkyl,(C1-10)alkylene, amino, amide, aryl, bicycloalkyl, carboxyl, carbonylgroup, ester group, halo, oxo, hydroxy, nitro, and the like. Also, eachof the substituents may be further substituted. When more than oneposition in a given structure may be substituted with more than onesubstituent selected from a specified group, the substituents may beeither the same or different at every position (for example, the moiety—N(R2)(R2)). Typically, when a structure may be optionally substituted,0-3 substitutions are preferred, and 0-1 substitutions are morepreferred. Most preferred substituents are those which enhance proteaseinhibitory activity or intracellular antiviral activity in permissivemammalian cells or immortalized mammalian cell lines, or which enhancedeliverability by enhancing solubility characteristics or enhancingpharmacokinetic or pharmacodynamic profiles as compared to theunsubstituted compound. Combinations of substituents and variablesenvisioned by this invention are only those that result in the formationof stable compounds. The term “stable”, as used herein, refers tocompounds which possess stability sufficient to allow manufacture andadministration to a mammal by methods known in the art. Typically, suchcompounds are stable at a temperature of 40° C. or less, in the absenceof moisture or other chemically reactive conditions, for at least aweek.

This invention also envisions the quaternization of any basicnitrogen-containing groups of the compounds disclosed herein. The basicnitrogen can be quaternized with any agents known to those of ordinaryskill in the art including, for example, lower alkyl halides, such asmethyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkylsulfates including dimethyl, diethyl, dibutyl and diamyl sulfates; longchain halides such as decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides; and aralkyl halides including benzyl and phenethylbromides. Water or oil-soluble or dispersible products may be obtainedby such quaternization.

As used herein, the compounds of this invention, including the compoundsof formula I are defined to include pharmaceutically acceptablederivatives or prodrugs thereof. A “pharmaceutically acceptablederivative or prodrug” means any pharmaceutically acceptable salt,ester, salt of an ester, or other derivative of a compound of thisinvention which, upon administration to a recipient, is capable ofproviding (directly or indirectly) a compound of this invention or aninhibitorily active metabolite or residue thereof. Particularly favoredderivatives and prodrugs are those that increase the bioavailability ofthe compounds of this invention when such compounds are administered toa mammal (e.g., by allowing an orally administered compound to be morereadily absorbed into the blood) or which enhance delivery of the parentcompound to a biological compartment (e.g., the brain or lymphaticsystem) relative to the parent species.

Salts derived from appropriate bases include alkali metal (e.g.,sodium), alkaline earth metal (e.g., magnesium), ammonium andN—(C₁₋₄alkyl)₄ ⁺ salts.

The compounds of this invention contain one or more asymmetric carbonatoms and thus occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be of the R or Sconfiguration. Although the specific compounds exemplified in thisapplication may be depicted in a particular stereochemicalconfiguration, compounds having either the opposite stereochemistry atany given chiral center or mixtures thereof are also envisioned.

The instant compounds may be prepared according to synthetic methods setforth, for example, in U.S. Pat. No. 6,319,946 to Hale et al., and in J.Med. Chem. 36, 288-291 (93), the disclosures of which are incorporatedherein by reference in their entireties, together with procedures of thetype described below.

A representative synthesis can be used when preparing variations of X′.Here instead of being sulfonylated, amino alcohol 2 can be N-protectedby a group that is not removed by removing P, for example P is Boc andP′ is Carbobenzyloxy. The di-protected 7 is then deprotected to give 8which is reacted as above to give 9. Following deprotection of 9 variousX′ groups may be introduced via the activated sulfonyl derivatives in asimilar fashion as described above.

An example of a synthesis of X with a third fused ring is shown below.This olefinic tricyclic system has already been described by McElvain,et al. JACS 77, 5601 (1955). Anti-Markownikov addition of water acrossthe double bond using standard conditions can provide the targetalcohol. It is noteworthy that these authors showed that theunsubstituted tricyclic system had unusual acid stability, which mayhelp prolong the activity of our target compounds.

The synthesis of a bicyclo[2.2.0] system can proceed in a similarfashion as has been described Padias, et al. J.O.C. 52, 5305 (1987) fora homologous analog. R can either be H or a protecting group such asbenzyl that can subsequently be removed under standard conditions.Protic (e.g. toluenesulfonic) or Lewis (e.g. scandium triflate) acidscan be used for the condensation.

The synthesis of a representative phosphorus containing bicycledescribed herein. Similar chemistry has been described by Arnold, et al.In Ang. Chem. 70, 539 (1958) and Dankiewicz, et al. in JACS 101, 7712(1979). The R group in the target shown may either be H

or a protecting group such as benzyl that can subsequently be removed.

Additional synthetic methods for preparing the compounds of theinvention are provided below.

Pharmaceutical Compositions

The compounds of the present invention may be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. Included among such acid salts, for example, are the following:acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate,bisulfate, butyrate, citrate, camphorate, camphorsulfonate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate,hexanoate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate,2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate and undecanoate.

Other pharmaceutically acceptable salts include a salt with an inorganicbase, organic base, inorganic acid, organic acid, or basic or acidicamino acid. Inorganic bases which form the instant pharmaceuticallyacceptable salts include alkali metals such as sodium or potassium,alkali earth metals such as calcium and magnesium or aluminum, andammonia. Organic bases which form the instant pharmaceuticallyacceptable salts include trimethylamine, triethylamine, pyridine,picoline, ethanolamine, diethanolamine, triethanolamine,dicyclohexylamine. Inorganic acids which form the instantpharmaceutically acceptable salts include hydrochloric acid, hydroboricacid, nitric acid, sulfuric acid, and phosphoric acid. Organic acidsappropriate to form the salt include formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid. Basic amino acids toform the salt include arginine, lysine and ornithine. Acidic amino acidsto form the salt include aspartic acid and glutamic acid.

The instant invention also contemplates compositions which can beadministered orally or non-orally in the form of, for example, granules,powders, tablets, capsules, syrup, suppositories, injections, emulsions,elixir, suspensions or solutions, by mixing these effective components,individually or simultaneously, with pharmaceutically acceptablecarriers, excipients, binders, diluents or the like.

The compounds of the present invention-are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of theseindividuals. The present invention may be useful in the treatment ofmammals infected with viruses whose existence is mediated by, or dependsupon, the protease enzyme. Conditions which may be prevented or treatedwith the compounds of the present invention, especially conditionsassociated with HIV and other pathogenic retroviruses, include AIDS,AIDS-related complex (ARC), progressive generalized lymphadenopathy(POL), as well as chronic CNS diseases caused by retroviruses, such as,for example HIV-mediated dementia and multiple sclerosis.

As a solid formulation for oral administration, the instant compositionmay be in the form of powders, granules, tablets, pills and capsules. Inthese cases, the instant compounds can be mixed with at least oneadditive, for example, sucrose, lactose, cellulose sugar, mannitol,maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins,tragacanth gum, gum arabic, gelatins, collagens, casein, albumin,synthetic or semi-synthetic polymers or glycerides. These formulationscan contain, as in conventional cases, further additives, for example,an inactive diluent, a lubricant such as magnesium stearate, apreservative such as paraben or sorbic acid, an anti-oxidant such asascorbic acid, tocopherol or cysteine, a disintegrator, a binder, athickening agent, a buffer, a sweetener, a flavoring agent and aperfuming agent. Tablets and pills can further be prepared with entericcoating.

As used herein, “non-orally” includes subcutaneous injection,intravenous injection, intramuscular injections, intraperitonealinjection or instillation. Injectable preparations, for example, sterileinjectable aqueous suspensions or oil suspensions can be prepared byknown procedures in the fields concerned, using a suitable dispersant orwetting agent and suspending agent. The sterile injections may be, forexample, a solution or a suspension, which is prepared with a non-toxicdiluent administrable non-orally, such as an aqueous solution, or with asolvent employable for sterile injection. Examples of usable vehicles oracceptable solvents include water, Ringer's solution and an isotonicaqueous saline solution. Further, a sterile non-volatile oil can usuallybe employed as solvent or suspending agent. A non-volatile oil and afatty acid can be used for this purpose, including natural or syntheticor semi-synthetic fatty acid oil or fatty acid, and natural or syntheticmono- or di- or tri-glycerides.

The instant pharmaceutical compositions may be formulated for nasalaerosol or inhalation and may be prepared as solutions in saline, andbenzyl alcohol or other suitable preservatives, absorption promoters,fluorocarbons, or solubilizing or dispersing agents.

Rectal suppositories can be prepared by mixing the drug with a suitablevehicle, for example, cocoa butter and polyethylene glycol, which is inthe solid state at ordinary temperatures, in the liquid state attemperatures in intestinal tubes and melts to release the drug.

Examples of liquid preparations for oral administration includepharmaceutically acceptable emulsions, syrups, elixirs, suspensions andsolutions, which may contain an inactive diluent, for example, water.

The pharmaceutical composition may be easily formulated for topicaladministration with a suitable ointment containing one or more of theinstant compounds suspended or dissolved in a carrier, which includemineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Inaddition, topical formulations can be formulated with a lotion or creamcontaining the active compound suspended or dissolved in a carrier.Suitable carriers include mineral oil, sorbitan monostearate,polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,benzyl alcohol and water.

Dosages of the instant compounds are dependent on age, body weight,general health conditions, sex, diet, dose interval, administrationroutes, excretion rate, combinations of drugs and conditions of thediseases treated, while taking these and other necessary factors intoconsideration. Generally, dosage levels of between about 10 μg per dayto about 5000 mg per day, preferably between about 100 mg per day toabout 1000 mg per day of the compound are useful in the prevention andtreatment of viral infection, including HIV infection. Typically, thepharmaceutical compositions of this invention will be administered fromabout 1 to about 5 times per day or alternatively, as a continuousinfusion. Such administration can be used as a chronic or acute therapy.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. A typicalpreparation will contain from about 5% to about 95% active compound(w/w). Preferably, such preparations contain from about 20% to about 80%active compound.

While these dosage ranges can be adjusted by a necessary unit base fordividing a daily dose, as described above, such doses are decideddepending on the diseases to be treated, conditions of such diseases,the age, body weight, general health conditions, sex, diet of thepatient then treated, dose intervals, administration routes, excretionrate, and combinations of drugs, while taking these and other necessaryfactors into consideration. For example, a typical preparation willcontain from about 0.05% to about 95% active compound (w/w). Preferably,such preparations contain from about 10% to about 80% active compound.The desired unit dose of the composition of this invention isadministered once or multiple times daily.

Accordingly, a preferred embodiment the instant invention alsocontemplates compositions and formulations comprising one or more of theinstant compounds in combination with one or more other HIV proteaseinhibitors, reverse transcriptase inhibitors, or non-nucleoside reversetranscriptase inhibitors.

The compounds of this invention may be administered to an uninfected orHIV-infected patient either as a single agent or in combination therapywith other anti-viral agents which interfere with the replication cycleof HIV in order to increase the therapeutic effect of these compounds.Thus, the present invention also relates to compositions comprising acompound of the present invention, and another antiretroviral compoundas a combined preparation for simultaneous, separate or sequential usein treatment of retroviral infections, in particular, in the treatmentof infections with multi-drug resistant retroviruses. Thus, to combat ortreat HIV infections, or the infection and disease associated with HIVinfections, such as Acquired Immunodeficiency Syndrome (ADS) or AIDSRelated Complex (ARC), the compounds of this invention may beco-administered in combination with for instance, binding inhibitors,such as, for example, dextran sulfate, suramine, polyanions, solubleCD4, PRO-542, BMS-806; fusion inhibitors, such as, for example, T20,T1249, 5-helix, D-peptide ADS-Ji; co-receptor binding inhibitors, suchas, for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK779; SHC-C (SCH351125), SHC-D, PRO-14ORT inhibitors, such as, forexample, foscamet and prodrugs; nucleoside RTIs, such as, for example,AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD, dOTC, DPC 817; nucleotideRTIs, such as, for example, PMEA, PMPA (tenofovir); NNRTIs, such as, forexample, nevirapine, delavirdine, efavirenz, 8 and 9-Cl TIBO(tivirapine), loviride, TMC-125, dapivirine, MKC-442, UC 781, UC 782,Capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-1366,TSAO, 4″-deaminated TSAO, MV150, MV026048; RNAse H inhibitors, such as,for example, SPI093V, PD126338; TAT inhibitors, such as, for example,RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L708906, L 731988, S-1360; protease inhibitors, such as, for example,amprenavir and prodrug GW908, ritonavir, nelfinavir, saquinavir,indinavir, lopinavir, palinavir, .BMS 186316, atazanavir, DPC 681, DPC684, tipranavir, AG1776, mozenavir, GS3333, KNI-413, KNI-272, L754394,L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU140135, TMC114, maslinic acid, U-140690; glycosylation inhibitors, suchas, for example, castanospermine, deoxynojirimycine.

The combination may in some cases provide a synergistic effect, wherebyviral infectivity and its associated symptoms may be prevented,substantially reduced, or eliminated completely.

The compounds of the present invention may also be administered incombination with immunomodulators (e.g., bropirimine, anti-human alphainterferon antibody, IL-2, methionine enkephalin, interferon alpha,HE-2000 and naltrexone) with antibiotics (e.g., pentamidine isothiorate)cytokines (e.g. Th2), modulators of cytokines, chemokines or thereceptors thereof (e.g. CCR5) or hormones (e.g. growth hormone) toameliorate, combat, or eliminate HIM infection and its symptoms.

Such combination therapy in different formulations may be administeredsimultaneously, separately or sequentially. Alternatively, suchcombination may be administered as a single formulation, whereby theactive ingredients are released from the formulation simultaneously orseparately.

The compounds of the present invention may also be administered incombination with modulators of the metabolism following application ofthe drug to an individual. These modulators include compounds thatinterfere with the metabolism at cytochromes, such as cytochrome P450.Some modulators inhibit cytochrome P450. It is known that severalisoenzymes exist of cytochrome P450, one of which is cytochrome P4503A4. Ritonavir is an example of a modulator of metabolism via cytochromeP450. Such combination therapy in different formulations, may beadministered simultaneously, separately or sequentially. Alternatively,such combination maybe administered as a single formulation, whereby theactive ingredients are released from the formulation simultaneously orseparately. Such modulator may be administered at the same or differentratio as the compound of the present invention. Preferably, the weightratio of such modulator vs. a compound of the present invention(modulator:compound of the present invention) is 1:1 or lower, morepreferably the ratio is 1:3 or lower, suitably the ratio is 1:10 orlower, more suitably the ratio is 1:30 or lower.

In order to enhance the solubility and/or the stability of the compoundsof formula I in pharmaceutical compositions, α, β, or γ cyclodextrins ortheir derivatives may be employed. Also co-solvents such as alcohols mayimprove the solubility and/or the stability of the compounds of formulaI in pharmaceutical compositions. In the preparation of aqueouscompositions, addition salts of the subject compounds may be moresuitable due to their increased water solubility.

Appropriate cyclodextrins are α, β, or γ-cyclodextrins (CDs) or ethersand mixed ethers thereof wherein one or more of the hydroxy groups ofthe anhydroglucose units of the cyclodextrin are substituted withC1-C6alkyl, such as methyl, ethyl or isopropyl, e.g. randomly methylatedβ-CD; hydroxy C16 alkyl, particularly hydroxyethyl, hydroxypropyl orhydroxybutyl; carboxy C1-C6alkyl, particularly carboxymethyl orcarboxyethyl; C1-C6alkyl-carbonyl, particularly acetyl; C1-C6alkyloxycarbonylC1-C6alkyl or carboxyC16alkyloxyC1-C6alkyl, particularlycarboxymethoxypropyl or carboxyethoxypropyl;C1-C6alkylcarbonyloxyC1-C6alkyl, particularly 2-acetyloxypropyl.Especially noteworthy as complexants and/or solubilizers are β-CD,randomly methylated β-CD, 2,6-dimethyl-β-CD, 2.-hydroxyethyl-β-CD,2-hydroxyethyl-γ-CD, hydroxy-propyl-γ-CD and(2-carboxymethoxy)propyl-β-CD, and in particular 2-hydroxy-propyl-β-CD(2-HP-β-CD).

The term mixed ether denotes cyclodextrin derivatives wherein at leasttwo cyclodextrin hydroxy groups are etherified with different groupssuch as, for example, hydroxy-propyl and hydroxyethyl.

The present compounds may be formulated in combination with acyclodextrin or a derivative thereof as described in EP-A-721,33 1.Although the formulations described therein are with antifungal activeingredients, they are equally relevant for formulating compounds of thepresent invention. The formulations described therein are particularlysuitable for oral administration and comprise an antifungal as activeingredient, a sufficient amount of a cyclodextrin or a derivativethereof as a solubilizer, an aqueous acidic medium as bulk liquidcarrier and an alcoholic co-solvent that greatly simplifies thepreparation of the composition. The formulations may also be renderedmore palatable by adding pharmaceutically acceptable sweeteners and/orflavors.

Other convenient ways to enhance the solubility of the compounds of thepresent invention in pharmaceutical compositions are described in WO94/05263, WO 98/42318, EP-A-499,299 and WO 97/44014, all incorporatedherein by reference.

More in particular, the present compounds may be formulated in apharmaceutical composition comprising a therapeutically effective amountof particles consisting of a solid dispersion comprising a compound offormula I, and one or more pharmaceutically acceptable water-solublepolymers.

The term “a solid dispersion” defines a system in a solid statecomprising at least two components, wherein one component is dispersedmore or less evenly throughout the other component or components. Whensaid dispersion of the components is such that the system is chemicallyand physically uniform or homogenous throughout or consists of one phaseas defined in thermodynamics, such a solid dispersion is referred to as“a solid solution”. Solid solutions are preferred physical systemsbecause the components therein are usually readily bioavailable to theorganisms to which they are administered.

The term “a solid dispersion” also comprises dispersions which are lesshomogenous throughout than solid solutions. Such dispersions are notchemically and physically uniform throughout or comprise more than onephase.

The water-soluble polymer in the particles is conveniently a polymerthat has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2%aqueous solution at 20° C.

Preferred water-soluble polymers are hydroxypropyl methylcelluloses(HPMC). HPMC having a methoxy degree of substitution from about 0.8 toabout 2.5 and a hydroxypropyl molar substitution from about 0.05 toabout 3.0 are generally water soluble. Methoxy degree of substitutionrefers to the average number of methyl ether groups present peranhydroglucose unit of the cellulose molecule. Hydroxypropyl molarsubstitution refers to the average number of moles of propylene oxidewhich have reacted with each anhydroglucose unit of the cellulosemolecule.

The particles as defined hereinabove can be prepared by first preparinga solid dispersion of the components, and then optionally grinding ormilling that dispersion. Various techniques exist for preparing soliddispersions including melt-extrusion, spray-drying andsolution-evaporation.

It may further be convenient to formulate the present compounds in theform of nanoparticles which have a surface modifier adsorbed on thesurface thereof in an amount sufficient to maintain an effective averageparticle size of less than 1000 nm. Useful surface modifiers arebelieved to include those which physically adhere to the surface of theantiretroviral agent but do not chemically bond to the antiretroviralagent.

Suitable surface modifiers can preferably be selected from known organicand inorganic pharmaceutical excipients. Such excipients include variouspolymers, low molecular weight oligomers, natural products andsurfactants. Preferred surface modifiers include nonionic and anionicsurfactants.

The present compounds may also be incorporated in hydrophilic polymersand applied as a film over many small beads, thus yielding a compositionwith good bioavailability which can conveniently be manufactured andwhich is suitable for preparing pharmaceutical dosage forms for oraladministration. The beads comprise a central, rounded or spherical core,a coating film of a hydrophilic polymer and an antiretroviral agent anda seal-coating polymer layer. Materials suitable for use as cores arepharmaceutically acceptable and have appropriate dimensions andfirmness. Examples of such materials are polymers, inorganic substances,organic substances, saccharides and derivatives thereof. The route ofadministration may depend on the condition of the subject, co-medicationand the like.

The instant compounds and compositions retain inhibitory activity, orpotency, over a broad spectrum of related but non-identical retroviralproteases. Accordingly, in another preferred embodiment, the instantinvention includes methods for treating or preventing viral infections.Treating or preventing refers to alleviating or hindering symptoms oreffects of a viral infection in an infected animal, such as a mammal,particularly a human. Treating includes prophylaxis as well as thetreatment of viral infections or symptoms of viral infections. Theinstant methods comprise treating an animal with a therapeuticallyeffective amount of a compound or composition according to the instantinvention. According to a preferred embodiment, the viral infection isan HIV infection, preferably an mdrHIV infection.

Moreover, the instant compounds and compositions are particularlyeffective as inhibitors against drug resistant and mdrHIV strains andmulti-drug resistant HIV proteases (mdrPR). Accordingly, in anotherpreferred embodiment, the instant invention provides methods forinhibiting HIV protease, particularly drug resistant and multi-drugresistant HIV proteases (mdrPR), with a therapeutically effective amountof a compound or composition according to the instant invention.

In relation to the above, the instant compounds may be used in vaccinesfor protecting individuals against viral, specifically, mdrHIVinfections. As such, the instant compounds may be employed as proteaseinhibitors as conventionally used in vaccines. In this regard, one ormore of the instant compounds may be combined with a pharmaceuticallyacceptable adjuvant conventionally employed in vaccines and administeredin prophylactically effective amounts to protect individuals over anextended period time against HIV infection.

The present invention also relates to novel compositions and a methodfor improving the pharmacokinetics of drugs which are metabolized bycytochrome P450 monooxygenase. In addition, the present inventionrelates to a novel composition and a method for inhibiting retroviralproteases and in particular for inhibiting human immunodeficiency virus(HIV) protease and a composition and a method for inhibiting aretroviral infection, in particular an HIV infection.

Use of Compounds of the Invention for “Boosting”

Surprisingly, it has been found that certain compounds of the inventionare not only potent inhibitors of HIV proteases, but also potentlyinhibit the cytochrome P450 isozyme (CYP3A4) that is mainly responsiblefor oxidative degradation of HIV protease inhibitors. In particular,compounds having a benzofuran moiety are potent inhibitors of CYP3A4. Inlight of this activity, these compounds are degraded only slowly andhave extended durations of action in vivo. Moreover, these compounds areuseful for “boosting” the activities of other HIV protease inhibitors byinhibiting CYP3A4-mediated degradation of those inhibitors.

In this connection, the present invention provides a method of improvingthe pharmacokinetics of a drug (or a pharmaceutically acceptable saltthereof) which is metabolized by cytochrome P450 monooxygenasecomprising coadministering a compound of the instant invention or apharmaceutically acceptable salt thereof. When administered incombination, the two therapeutic agents can be formulated as separatecompositions which are administered at the same time or different times,or the two therapeutic agents can be administered as a singlecomposition. In one aspect, when therapeutic agents are administered incombination, the dosage used may be at the therapeutic dosage or atsub-therapeutic dosages.

Drugs which are metabolized by cytochrome P450 monooxygenase and whichbenefit from coadministration with a compound of the instant inventioninclude, but are not limited to, ritonavir, the immunosuppressantscyclosporine, FK-506 and rapamycin, the chemotherapeutic agents taxoland taxotere, the antibiotic clarithromycin and the HIV proteaseinhibitors A-77003, A-80987, MK-639, saquinavir, VX-478, AG1343,DMP-323, XM-450, BILA 2011 BS, BILA 1096 BS, BILA 2185 BS, BMS 186,318,LB71262, SC-52151, SC-629(N,N-dimethylglycyl-N-(2-hyrdoxy-3-(((4-methoxyphenyl)sulphonyl)(2-methyl-propyl)amino)-1-(phenylmethyl)propyl)-3-methyl-L-valinamide),KNI-272, CGP 53437, CGP 57813 and U-103017.

In a preferred embodiment of the present invention, there is disclosed amethod for improving the pharmacokinetics of an HIV protease inhibitor(or a pharmaceutically acceptable salt thereof) which is metabolized bycytochrome P450 monooxygenase comprising coadministering a compound ofthe instant invention or a pharmaceutically acceptable salt thereof.Such a combination of a compound of the instant invention or apharmaceutically acceptable salt thereof and an HIV protease inhibitoror a pharmaceutically acceptable salt thereof which is metabolized bycytochrome P450 monooxygenase is useful for inhibiting HIV protease inhumans and is also useful for inhibition, treatment or prophylaxis of anHIV infection or AIDS (acquired immune deficiency syndrome) in humans.When administered in combination, the two therapeutic agents can beformulated as separate compositions which are administered at the sametime or different times, or the two therapeutic agents can beadministered as a single composition.Preparation of Sulfonyl Chlorides

2,3-Dihydrobenzofuran-5-sulfonyl chloride

Prepared from commercially available 2,3-dihydrobenzofuran as describedin the patent EP 0583960A2.

3.56 g (29.6 mmol) 2,3-dihydrobenzofuran was added to a slurry of 5.44 g(35.5 mmol) sulfur trioxide-N,N-dimethylformamide complex in 12 mL1,2-dichloroethane under argon. The reaction was heated to 85° C. for 1hour and then cooled to room temperature. Thionyl chloride (2.6 mL, 35.5mmol, 1.2 eq) was added dropwise and the reaction was slowly heated overthe course of one hour, by which time it had reached 75° C. The mixturewas allowed to cool to room temperature and 100 mL of methylene chlorideand 100 mL water were added. The organic extract was separated, driedover magnesium sulfate, filtered and evaporated to afford 6.56 g (100%)of 2,3-dihydrobenzofuran-5-sulfonyl chloride as a tan oil. (TLC Rfchloroform/hexanes=1/1)

Benzofuran-5-sulfonyl chloride

2,3-Dihydrobenzofuran-5-sulfonyl chloride 300 mg (1.37 mmol) wasdissolved in 2 mL of benzene. N-bromosuccinimide 244 mg (1.37 mmol) andAIBN 3 mg were added to the solution and the reaction was heated at 80°C. for 1 hour. The reaction was allowed to come to room temperature,filtered and the benzene removed under vacuum. The residue was purifiedby chromatography on silica gel with hexanes/methylene chloride=2/1 toafford 237 mg (80%) of the pure material (TLC). The final product can berecrystallized from ether/hexanes to provide colorless crystals withm.p. 48.5-50.6° C.

3-Methyl-2,3-dihydrobenzofuran was synthesized as described in theliterature starting from 2-iodophenol (Organic Synthesis, CV3, 418; L.W. Menapace and H. G. Kuivila, J. Amer. Chem. Soc., 86, 3047 (1964), andreferences cited therein).

3-Methyl-2,3-dihydrobenzofuran-5-sulfonyl chloride

Prepared from 3-methyl-2,3-dihydrobenzofuran as Described in the PatentEP 0583960A2.

12.03 g (90.4 mmol) 3-methyl-2,3-dihydrobenzofuran was added to theslury of 15.22 g (99.5 mmol) sulfur trioxide-N,N-dimethylformamidecomplex in 25 mL 1,2-dichloroethane under argon. The reaction was heatedto 85° C. for 1 hour and cooled to room temperature. Thionyl chloride(7.9 mL, 108.5 mmol) was added dropwise and the reaction was slowlyheated over the course of one hour, by which time it had reached 75° C.The mixture was allowed to cool to room temperature and 150 mL ofmethylene chloride and 150 mL water were added. The water layer wasextracted with methylene chloride (2×30 mL). The organic extracts werecombined, washed by 100 mL water, dried over magnesium sulfate, filteredand evaporated to afford 20.4 g (97%) of tan oil pure by TLC(chloroform/hexanes=1/1).

2-bromo-3-bromomethyl-benzofuran-5-sulfonyl chloride

3-Methyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (5.0 g, 21.5 mmol)was dissolved in 1,2-dichloroethane (75 mL). To this was addedN-bromosuccinimide (NBS) (11.5 g, 64.5 mmol) followed byazoisobutyronitrile (106 mg, 0.6 mmol). The reaction mixture was heatedat 40° C. After 1.5 h another 3.8 g of NBS was added. After anadditional 3 h at 40° C. the reaction mixture was 75 mL of cold water.The aqueous layer was extracted with dichloromethane (2×10 mL), thecombined organic extract washed with 5% sodium thiosulfate, water andbrine. Concentrating the organic layer followed by crystallization fromethyl acetate/hexane provided 6.0 g (73%) of product as a whitecrystalline solid, m.p. 128.6-129.8° C. TLC (chloroform/hexanes=1/1)

3-Bromomethyl-benzo[d]isoxazole

(Mohareb et al., Z.Naturforsch.B 1067 (1990); Henke, et al., J. Med.Chem. 2706 (1997) Benzo[d]isoxazol-3-yl-bromo-acetic acid [(J. Med.Chem. 5428 (2003), Chem. Pharm. Bull, 3498 (1978)] was slowly heatedunder argon with stirring to 130° C. and held there for 30 minutes.Copious gas evolution was observed during this time. The reaction wascooled to room temperature and the resulting brown crystals werefiltered off and purified via column chromatography (hexanes), (2.3 g,70% yield).

3-Bromomethyl-benzo[d]isoxazole-5-sulfonyl chloride

Chlorosulfonic acid (1.5 ml, 22 mmol) was slowly added to3-Bromomethyl-benzo[d]isoxazole (1.0 g, 4.7 mmol) at RT under argon. Thereaction was heated at 90° C. for 12 h and then left at RT for 6 h. Theresulting viscous oil was quenched over ice, extracted with EtOAc, driedover MgSO4 and concentrated in vacuo to a brown oil (1.17 g, 80% yield).

1-(3-methyl-indazol-1-yl)-ethanone [Chem. Ber. 53; 1204 (1920)]

3-Methylindazole (1.00 g, 7.6 mmol) (J. Med. Chem. 2706 (1997)] wasdissolved in 10 ml THF and stirred at room temperature under a blanketof argon. Pyridine (0.64 ml, 7.9 mmol) was added, followed by Ac₂O (0.79ml, 8.3 mmol) and catalytic DMAP (90 mg, 0.7 mmol). The reactionproceeded for 2 h and was then partitioned between 1N HCl anddichloromethane. The organic phase was dried over MgSO4 and concentratedunder vacuum to a tan solid (1.2 g, 91% yield).

3-Methyl-1H-indazole-5-sulfonyl chloride

To chlorosulfonic acid (0.38 ml, 5.7 mmol) under a blanket of argon inan ice bath was added 1-(3-methyl-indazol-1-yl)-ethanone (200 mg, 1.1mmol). The reaction was allowed to warm to room temperature and then washeated at 70° C. for 45 min. The reaction was cooled to roomtemperature, slowly quenched over ice and extracted withdichloromethane. The organic phase was dried over MgSO₄ and concentratedin vacuo to a tan solid (160 mg, 0.7 mmol, 61% yield). TLC: R_(f) 0.2(1:4 ethyl acetate: hexane). MS 229 MH⁺.

3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamicacid benzyl ester 16

To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butylester² 15 (94 g, 0.279 mol) in 600 ml THF was added a solution of Na₂CO₃(32.5 g, 0.307 mol) in 200 ml H₂O. Cbz-chloride (52.4 g, 0.307 mol, 1.1eq) dissolved in THF (100 mL) was added dropwise to the above mixture at5-10° C. (ice bath) over the course of I h, after which time the mixturewas stirred for additional 2 h at 10° C. Ethyl acetate (1000 ml) wasthen added to the reaction mixture, the organic layer was separated,washed sequentially by aqueous NaHCO₃, KHSO₄ and brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The oily residuecrystallized from EtOAc/hexane to give3-tert-butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamicacid benzyl ester 16 (101 g, 77%) as a white solid, m.p. 79-81° C.2. Ghosh, et al. J. Org. Chem. 63; 18; 6146-6152 (1998).

[3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamicacid benzyl ester 18

(3-tert-Butoxycarbonylamino-2-hydroxy-4-phenyl-butyl)-isobutyl-carbamicacid benzyl ester 16 (7.54 g, 15 mmol) and 35 ml of 4M HCl in dioxanewere stirred 30 min under an argon atmosphere. The mixture wasconcentrated in vacuo, and co-evaporated twice with dichloromethane. Theresidue was dissolved in dichloromethane (50ml) andN,N-diisopropylethylamine (6.1 ml, 35 mmol), and carbonic acid2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester 17(4.88g, 18 mmol) was added. The reaction mixture was stirred overnight,and then concentrated in vacuo. The residue was diluted withdichloromethane, and sequentially washed with brine, 10% KHSO4, brine,saturated NaHCO₃, and brine, then dried over MgSO₄, and concentrated invacuo. The oily residue was purified by flash chromatography using 70:30ethyl acetate hexane as eluant, to give[3-(Hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamicacid benzyl ester 18 (5.8 g, 73%) as a white solid. TLC: R_(f) 0.56 (7:3ethyl acetate: hexane). MS 527 (MH)⁺.

Related procedure: Ghosh, et al. BMCL 687 (1998).

(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester 19

A mixture of[3-(hexahydro-furo[2,3-b]furan-3-yloxycarbonylamino)-2-hydroxy-4-phenyl-butyl]-isobutyl-carbamicacid benzyl ester 18 (5.5 g, 10.4 mmol) and 550 mg of 10% Pd/C in 130 mlof ethanol was stirred under a hydrogen atmosphere overnight. Thecatalyst was removed by filtration through Celite®, and the solution wasevaporated to dryness to yield(1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester 19 (4.0 g, 97%) as a white solid.TLC: R_(f) 0.36 (5:15:85 triethylamine:methanol:ethyl acetate). MS 393(MH)⁺.

Preparation of Target Compounds.

Method 1

The sulfonyl chloride is reactedwith(1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester 19 in methylene chloride andaqueous NAHCO3 and stirred at room temperature until reaction complete.

{3-[(Benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

Benzofuran-5-sulfonyl chloride 148 mg (0.68 mmol) was dissolved in 5 mLof methylene chloride.(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester 19 (244 mg, 0.62 mmol) was addedfollowed by 0.63 mL 10% NaHCO3 solution (0.75 mmol). The reaction wasstirred at room temperature for 16 hours. The organic phase wasseparated and loaded onto silica gel in methylene chloride. The excessof benzofuran-5-sulfonyl chloride was washed out by several portions ofmethylene chloride. The final product was obtained by eluting with 3/1ethyl acetate/methylene chloride. Concentration in vacuo afforded 350 mg(98.5% yield) of the final product with HPLC purity of >97% (220 nm).The product can be recrystallized from ethyl acetate/hexanes to getcolorless crystals m.p. 122-124° C. MS 573 (MH)⁺.

{1-Benzyl-3-[(2-bromo-3-bromomethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamicacid hexahydro-furo [2,3-b]furan-3-yl ester

2-Bromo-3-bromomethyl-benzofuran-5-sulfonyl chloride (5) (1.75 g, 4.5mmol) was dissolved in 50 mL of methylene chloride.(1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acidhexahydro-furo[2,3-b]furan-3-yl ester 19 (1.75 g, 4.5 mmol) was addedfollowed by 4.5 mL 10% NaHCO3 solution (5.4 mmol). The reaction wasstirred at room temperature for 16 hours. The organic phase waspartitioned between methylene chloride (150 mL) and water (100 mL), theorganic phase separated, dried over magnesium sulfate, filtered andconcentrated under vacuum. The final product was chromatographed onsilica using 1/1 ethyl acetate/methylene chloride eluent to yield 2.79 gof the product (83%) as white crystals. (>95% HPLC). MS 663, 665 (M-H)

Method 2.

The haloalkyl aromatic compound is reacted with excess amine or anothernucleophile in the presence of excess base such as triethylamine.

{3-[(3-Aminomethyl-2-bromo-benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

Bis-THF-core-2-bromo-3-bromomethyl-benzofuran-5-sulfonyl (6) (2.02 g,2.71 mmol) was dissolved in 100 mL methylene chloride and added dropwiseto 100 mL of 7N ammonia in methanol at 4° C. was added. After additionwas complete, the reaction was stirred at room temperature for 16 hours.HPLC analysis indicated no remaining starting material. The volatilecomponents were removed under vacuum and the residue was used in thenext step without further purification. A sample from a separate run waspurified by prep HPLC. MS 680, 682 (MH+)

Method 3.

The bromo substituent on the heteroaromatic ring is removed byhydrogenation over 10% Pd/C in the presence of triethylamine.

{3-[(3-Aminomethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamicacid hexahydro-furo [2,3-b]furan-3-yl ester

Bis-THF-core-2-bromo-3-aminomethyl-benzofuran-5-sulfonyl (7) from theprevious reaction was dissolved in 150 mL tetrahydrofuran. 10% Pd/C (100mg) and triethylamine 0.76 mL were added. The reaction was stirred underhydrogen at room temperature. Once there was no starting 7 left in thereaction (HPLC), the reaction mixture was filtered and concentrated invacuo. The final product can be used directly in the next step. A samplefrom a separate run was purified by prep HPLC. MS 602 (MH+).

Method 4.

Aminoalkyl substituted compounds are acylated or sulfonylated using asuitable activated carboxylic or sulfonic acid derivative in thepresence of a base such as triethylamine. They can be alkylated using anactivated alcohol derivative or halide or by reductive amination with analdehyde or ketone.

(3-{[3-(Benzoylamino-methyl)-benzofuran-5-sulfonyl]-isobutyl-amino}-1-benzyl-2-hydroxy-propyl)-carbamicacid hexahydro-furo [2,3-b]furan-3-yl ester

{3-[(3-Aminomethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester from the previous step (20mg, 33 umol) was dissolved in 0.5 mL THF. 5.8 uL (50 umol) benzoylchloride and 7 uL (50 umol) triethylamine were added and the reactionwas stirred at room temperature for 1 h. The reaction mixture waspurified by prep TLC on the silica gel plate with ethylacetate/hexanes=2/1 to afford 12 mg (17 umol, 52%) of product. MS 706(MH+).

Method 5.

The heterocyclic ring is built up from a condensation reaction of asuitably substituted aromatic ring with a bidentate nucleophile such ashydrazine or hydroxylamine.Step 1

551-Benzyl-3-[(3-cyano-4-fluoro-benzenesulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2C12 (4 mL) was added4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed byNaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. Thereaction mixture was diluted with ethyl acetate (25 mL) and washed withwater, brine and dried with Na2SO4 and concentrated to furnish crudeproduct (240 mg). The crude product was purified by columnchromatography using 1/1 ethyl acetate/hexane to provide 200 mg product(92% yield).Step 2

{3-[(3-Amino-1H-indazole-5-sulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

{1-Benzyl-3-[(3-cyano-4-fluoro-benzenesulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester (200 mg, 0.35 mmol) wasdissolved in EtOH (6.0 mL) and CH2C12 (4.0 mL) Hydrazine was added(0.066 mL, 2.1 mmol) and the reaction heated at 50° C. for 12 h. Thereaction mixture was concentrated and purified by prep TLC usingMeOH/CHCl3 (1/9) to furnish the product (140 mg, 70% yield). R_(f) 0.5MeOH/CHCl3 (1/9). MS 588 (MH⁺).

Method 6.

The sulfonyl chloride was first reacted with(1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butylester using the conditions of Method 1. The Boc group was then removedunder acidic conditions and the resulting amine reacted with2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester inthe presence of a base such as diisopropylethylamine.Step 1

{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamicacid tert-butyl ester

To (1-Benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid tert-butylester 15 (60 mg, 0.18 mmol) and 3-methyl-1H-indazole-5-sulfonyl chloride(50 mg, 0.22 mmol) in 2 mL dichloromethane was added a 70 ul solution ofa saturated NaHCO3 and 30 mg NaHCO3 and stirred overnight. The productwas purified by preparative TLC using 1:1 ethyl acetate: hexane to give95 mg product (99% yield). MS 531 (MH⁺).Step 2.

{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

{1-Benzyl-2-hydroxy-3-[isobutyl-(3-methyl-1H-indazole-5-sulfonyl)-amino]-propyl}-carbamicacid tert-butyl ester (25 mg, 0.047 mmol) was added to a solution of 4NHCl in dioxane (0.25 mL). Material precipitated out so 800 uL conc. HClwas added and the reaction heated at reflux for 2 h. The resultingsolution was concentrated under vacuum and concentrated 2 additionaltimes from 1 mL methylene chloride. This crude amine was dissolved in0.5 mL methylene chloride and diisopropylethylamine (80 uL, 0.46 mmol)was then added. To this solution was added carbonic acid2,5-dioxo-pyrrolidin-1-yl ester hexahydro-furo[2,3-b]furan-3-yl ester(16 mg, 0.055 mmol) and the reaction stirred overnight. The reaction wasconcentrated under vacuum and purified by preparative HPLC. MS 587(MH⁺).

Method 7.

Side chains with oxidizable groups such as sulfides were oxidized with asuitable reagent such as hydrogen peroxide. Side chains with reduciblegroups such as esters could be reduced with a reducing agent such asLAH.

(1-Benzyl-3-{[3-(butane-1-sulfinylmethyl)-benzofuran-5-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester

{1-Benzyl-3-[(3-butylsulfanylmethyl-benzofuran-5-sulfonyl)-isobutyl-amino]-2-hydroxy-propyl}-carbamicacid hexahydro-furo[2,3-b]furan-3-yl ester (10 mg, 14.8 umol) wasdissolved in 0.5 mL THF and 150 uL of 50% hydrogen peroxide in water wasadded. The reaction was stirred at room temperature and the progress wasmonitored by HPLC analysis. After 3.5 hours there was no startingmaterial left in the reaction mixture. The reaction was partitionedbetween 20 mL ethyl acetate and 20 mL 0.1 N sodium thiosulfate solution.The organic phase was separated, washed with 15 mL brine and dried overanhydrous sodium sulfate. Filtration followed by concentration undervacuum afforded 10 mg (97%) of the final HPLC pure product. MS 691(MH+).

HPLC Conditions:

Waters column YMC ODS-AQ S-3 120A 3.0×100 mm

Mobile phase A—water, 0.1% TFA

Mobile phase B—methanol, 0.1% TFA

Flow 0.75 mL/min

Gradient:

0-3 min—20% B

3-16 min—20-85% B

16-20 min—85% B

Detection by UV at 222 m TABLE 1 Benzofuran Synthesis

Temp HPLC Compound 2- 3- Method Reagents Solvent ° C. Time Yield MH+ RT101 H H 1 Benzofuran-5- DCM RT 16 h 99% 573 13.9 sulfonyl chloride min.102 Me H 1 2-Methyl- DCM RT 16 h 83% 587 15.1 benzofuran-5- min.sulfonyl chloride 103 H Me 1 3-Methyl- DCM RT 16 h 87% 587 14.9benzofuran-5- min. sulfonyl chloride 104 CH2Br H 1 2-bromomethyl- DCM RT16 h 79% 663, 14.8 benzofuran-5- 665 min. sulfonyl chloride (M − H) 105CH2NH2 H 2 Ammonia in MeOH MeOH RT 18 h 99% 602 10.6 min. 106 CH2NHCH H4 Acetic anhydride THF RT 16 h 100%  644 12.8 (Me)CO2Et min. 107 H CH2NH4 Acetic anhydride THF RT  2 h 56% 644 12.8 COMe min. 108 H CH2-4- 3 H2,Pd/C THF RT  2 h 67% 672 12.8 morpholino min. 109 H CH2-1- 3 H2, Pd/CTHF RT 1.5 h  98% 670 11.8 piperidino min. 110 H CH2NH 3 H2, Pd/C THF RT 2 h 68% 716 CH2 CO2tBu 111 H CH2S(O)Bu 7 H2O2 THF RT 3.5 h  97% 69114.0 min. 112 H CH2NH 4 Ethyl THF RT 16 h 75% 674 13.6 CO2Etchloroformate, min. Et3N 113 H CH2NH 4 Propionic acid, THF RT  1 h 73%658 13.0 COEt DCC, Et3N min. 114 H CH2NH 4 Benzoyl chloride, THF RT  1 h51% 706 13.5 COPh Et3N min. 115 H CH2NH 4 Isopropylsulfonyl DCM RT 24 h77% 708 13.5 SO2iPr chloride, NaHCO3 min. 116 H CH2NHCO 4 Cbz-Gly-OH,THF + D RT 16 h 49% 793 14.6 CH2NHCbz TBTU, Et3N MF min. 117 H CH2NH(CH3 H2, Pd/C THF RT  3 h 51% 707 10.8 2)2-2- min. pyridinyl 118 H CH2NHCO-4 Nicotinoyl chloride, THF RT 16 h 34% 707 12.5 3-pyridyl Et3N min. 119H CH2NH 4 HOCOCH2SCH2 THF RT 16 h 53% 766 14.8 COCH2S Ph, TBTU, Et3Nmin. CH2Ph 120 H CH2NHCOC 7 H2O2 THF RT 24 h 96% 782 13.7 H2S(O)CH2 min.Ph 121 CH2NH H 4 Ethyl THF RT 18 h 71% 674 13.2 CO2Et chloroformate,min. Et3N 122 H CH2OCO 3 H2, Pd/C THF RT  4 h 67% 645 16.0 CH3 min. 123H CH2OCH3 3 H2, Pd/C THF RT 2.5 h  75% 617 15.7 min. 124 H CH2OH 3 H2,Pd/C THF RT 2.5 h  62% 603 14.6 min. 125 H CH2NHCO- 4 2-Furoic acid,THF + D RT 18 h 50% 696 15.3 2-furanyl TBTU, Et3N MF min. 126 HCH2N(CO2Et) 4 Ethyl THF RT 16 h 84% 732 11.8 CH2CH2O chloroformate min.Me Et3N 127 Br CH2Br 1 2-bromo-3- DCM RT 16 h 77% 743, 15.4 bromomethyl-745, min. benzofuran-5- 747 sulfonyl chloride 128 Br CH2NH2 2 Ammonia inMeOH DCM RT 16 h 92% 680, 11.6 682 min. 129 Br CH2-4- 2 Morpholine EtOHRT 16 h 100%  750, 11.6 morpholino 752 min. 130 Br CH2SBu 2 BuSH, Et3NDCM RT 16 h 100%  753, 17.0 755 min. 131 Br CH2NHEt 2 EtNH2 DCM RT 16 h71% 708, 11.8 710 min. 132 Br CH2-1- 2 Piperidine DCM RT 16 h 72% 748,12.1 piperidino 750 min. 133 Br CH2NH 2 Gly-OtBu, DCM RT 144 h  83% 794,13.1 CH2 diisopropylethyl 796 min. CO2tBu amine 134 Br CH2NH(CH 22-(2-amino DCM RT 16 h 62% 2)2-2- ethyl)pyridine pyridinyl 135 Br CH2NH2 2-(ethylthio) DCM RT 16 h 84% 13.6 (CH2)2SEt ethylamine, Et3N min. 136Br CH2NH 2 2-methoxy DCM RT 16 h 74% 15.8 (CH2)2 ethylamine, Et3N min.OMe 137 Br CH2OCO 2 NaOAc, NaI Acetone 60 16 h 86% 17.1 CH3 min. 138 BrCH2OCH3 2 Et3N MeOH 65 10 h 95% 695, 17.0 697 min. 139 Br CH2OH 2 KHCO3MeOH 90  4 h 30% 683, 16.0 685 min. 140 CH2N H 2 Et2NH DCM RT 16 h 85%658 11.5 Et2 min. 141 CH2NH H 2 EtNH2 DCM + RT  4 h 84% 630 11.0 Et MeOHmin. 142 CH2-1- H 2 Piperidine DCM RT  4 h 93% 670 11.6 piperidino min.143 CH2-4- H 2 Morpholine DCM RT  4 h 98% 672 11.0 morpholino min. 144CH2NMe H 2 Methylethylamine DCM RT 3.5 h  87% 644 11.3 Et min. 145 CH2NHH 2 Benzylamine DCM RT 16 h 77% 692 11.9 CH2Ph min. 146 CH2SBu H 2 BuSH,Et3N DCM RT 16 h 49% 675 16.3 min. 147 H CH2NH2 3 H2, Pd/C THF RT  2 h85% 602 10.9 min. 148 H CH2SBu 3 H2, Pd/C THF RT  2 h 91% 675 16.1 min.149 H CH2NHEt 3 H2, Pd/C THF RT  1 h 44% 630 10.8 min. 150 H CH2NH(CH2)3 H2, Pd/C THF RT 11 h 60% 690 13.7 2SEt min. 151 H CH2NH 3 H2, Pd/C THFRT  1 h 92% 660 13.2 (CH2)2OMe min. 152 H CH2NHCO 4 3-Pyridylacetic THFRT 16 h 56% 721 11.7 CH2-3- acid, TBTU, Et3N min. pyridyl 153 H CH2NEt 4Ethyl THF RT  5 h 62% 702 16.8 CO2Et chloroformate, min. Et3N 154 HCH4NHCO 4 CCl2O, Et3N DCM 4 then 16 h 45% 673 14.8 NHCH2CH3 EtNH2 RTmin. 155 CH2S(O) H 7 H2O2 THF RT 24 h 62% 691 13.7 Bu min.

TABLE 2 Benzisoxazole Synthesis

Compound 3- Method Reagents Solvent Temp ° C. Time Yield MH+ 201 Me 13-Methylbenzisoxazole- CH2Cl2 RT 4 hr 65 588 5-sulfonyl chloride, NaHCO3202 CH2NHiPr 2 Isopropylamine Neat RT 30 min 80 645 203 CH2NH2 2NH3/1,4-dioxane THF 50 2 hr 70 603 204 CH2NHSO2iPr 4 2-propanesulfonylCH2Cl2 RT 12 hr 90 709 chloride, NaHCO3 205 CH2OAc 2 NaOAc, NaI Acetone60 48 hr 25 646 206 CH2CH(Me) 4 Ethyl pyruvate, AcOH/ RT 1 hr 52 703CO2Et NaBH3CN EtOH 207 CH2NHSO2Me 4 Methanesulfonyl CH2Cl2 RT 12 hr 100681 chloride, NaHCO3 208 CH2S(O)Bu 7 H2O2 THF RT 48 hr 86 714 (Na) 209CH2S-iPr 2 2-Propanethiol DMF RT 12 hr 80 662 210 CH2NMeSO2Me 4Methanesulfonyl CH2Cl2 RT 12 hr 68 695 chloride, NaHCO3 211 CH2NMeTs 4p-Toluenesulfonyl CH2Cl2 RT 12 hr 76 771 chloride, NaHCO3 212CH2NHCO2iPr 4 isopropyl succinimido CH2Cl2 RT 12 hr 81 689 carbonate,NaHCO3 213 CH2OH 2 Sodium acetate, NaI Acetone 55 12 hr 18 604 214CH2NHCOMe 4 Acetic anhydride, CH2Cl2 RT 12 hr 90 646 NaHCO3 215CH2OCOiPr 2 Isobutyric acid, NaI, Acetone reflux 10 hr 30 675 NaOH 216CH2-1-imidazole 2 Imidazole THF RT 12 hr 98 654 217 CH2NHCO2Et 4 Ethylchloroformate, CH2Cl2 RT 12 hr 93 676 NaHCO3 218 CH2OCOtBu 2Trimethylacetic acid, Acetone reflux 12 hr 100 688 NaI, NaOH 219CH2NHCH2CH2 2 Methoxyethylamine THF RT 5 hr 88 661 OMe 220 CH2NHCOiPr 4Isobutyric acid, TBTU, THF RT 4 hr 80 673 Et3N 221 CH2NHCOPh 4 Benzoylchloride, Et3N THF RT 48 hr 70 707 222 CH2NHCO2Pr 4 Propylchloroformate, CH2Cl2 RT 2 hr 80 690 NaHCO3 223 CH2NHSO2Et 4Ethanesulfonyl chloride, CH2Cl2 RT 12 hr 80 695 NaHCO3 224CH2NH(CH2)2-2- 2 2-(2- THF RT 12 hr 70 708 pyridinyl Aminoethyl)pyridine225 CH2N((CH2)2OMe) 4 Ethyl Chloroformate, CH2Cl2 RT 12 hr 80 733 CO2EtNaHCO3 226 CH2NHCH2CH2 2 2-(Ethylthio)ethylamine THF 55 12 hr 40 691 SEt227 CH2N((CH2)2OMe) 4 Ethanesulfonyl chloride, CH2Cl2 RT 48 hr 70 754SO2Et NaHCO3 228 CH2NHCH2CF2 2 2,2,3,3,3- THF 55 12 hr 60 735 CF3Pentafluoropropyl amine 229 CH2NHCH2CF3 2 2,2,2- THF 55 12 hr 70 685Trifluoroethylamine 230 CH2NHCH2CH2 2 2-Phenoxyethylamine, THF RT 12 hr80 724 OPh Et3N 231 CH2NHBu 2 n-Butylamine THF RT 12 hr 80 658 (M − 1)232 CH2NHCH2Ph 2 Benzyl amine THF RT 12 hr 80 693 233 CH2SCH2CF3 22,2,2- DMF RT 12 hr 60 702 Trifluoroethanethiol, NaHCO3 234 CH2NHCOCF3 4Trifluoroacetic CH2Cl2 RT 48 hr 70 699 anhydride, Et3N 235 CH2NHcyclo 2Cyclopentylamine THF RT 12 hr 80 716 pentyl formate 236 CH2NHCH2CH2 2N-Boc-ethylenediamine THF RT 12 hr 73 746 NHBoc 237 CH2NH(CH2)3-1- 21-(3-aminopropyl)-2- THF RT 24 hr 47 728 pyrollidinone pyrolidinone 238CH2NHCH2cyclo 2 Cyclohexane THF RT 5 hr 80 698 hexyl methylamine (M − 1)239 CH2-4-morpholino 2 Morpholine THF RT 1 hr 61 673 240 CH2NHCO-2- 42-Furoyl chloride, Et3N, CH2Cl2 RT 2 hr 87 697 furanyl DMAP 241CH2NHCH2-2- 2 2- THF RT 12 hr 45 694 pyridinyl (aminomethyl)pyridine 242CH2NHCH2-4- 2 4-aminomethyl-2- THF RT 12 hr 47 714 (2-methylthiazole)methylthiazole, Et3N 243 CH2SO2Me 2 Sodium EtOH 60 2 hr 43 666methanesulfinate 244 CH2OCH3 2 Succinimide sodium salt MeOH RT 12 hr 48618 245 CH2NHCOCF2 4 CF3CF2CO2H/ CH2Cl2 RT 4 hr 42 749 CF3 (COCl)2,Et3N, DMAP 246 CH2OCH2CF3 2 CF3CH2OH, KHCO3 DMF 60 1 hr 50 686 247CH2N(Ac)CH2 4 CH3COCl, Et3N, CH2Cl2 RT 2 hr 50 727 CF3 DMAP 248CH2NHCH2-5- 2 1-Benzofuran-5- THF RT 12 hr 80 733 benzofuranylylmethylamine 249 OH 1 3-chlorobenzisoxazole CH2Cl2 RT 12 hr 25 5905-sulfonyl chloride, NaHCO3 250 CH2Br 1 3-Bromomethylbenz CH2Cl2 RT 2 hr24 666, 668 isoxazole-5-sulfonyl chloride, NaHCO3 251 CH2CO2Me 13-Methoxycarbonyl CH2Cl2 RT 1.5 hr 20 646 methylbenzisoxazole-5-sulfonyl chloride, NaHCO3 252 CH2NHMe 2 MeNH2 EtOH RT 30 min 98 617 253CH2NMe2 2 Me2NH.HCl Diisopropyl RT 48 hr 80 631 ethylamine 254 CH2CN 2NaCN THF 50 12 hr 40 613 255 CH2SCH2Ph 2 Benzyl mercaptan, DMF RT 12 hr50 710 K2CO3 256 CH2SPh 2 Benzenethiol Acetone RT 12 hr 70 696 257CH2N(CH2-2- 2 2- THF RT 24 hr 40 786 pyridinyl)2 (aminomethyl)pyridine258 CH2SCN 2 KSCN ETOH/THF 50 12 hr 100 645 259 CH2N(Et)CH2 23-(Ethylamino)propio THF 40 12 hr 70 684 CH2CN nitrile, Et3N 260CH2SC(NH)NH2 2 Thiourea DMF RT 12 hr 70 662 261 CH2-1-pyrrolidine 2Pyrrolidine THF RT 1 hr 56 657 262 CH2-4-tosyl 2 p-Toluenesulfinic acidEtOH 60 2 hr 72 742 sodium salt 263 CH2-1-succinimido 2 Succinimide, NaHTHF RT 10 hr 60 685 264 CH2I 2 NaI DMF 70 6 hr 45 736 (Na) 265 NHAc 4Acetic anhydride CH2Cl2 RT 12 hr 53 631 266 NHCO2Et 4Ethylchloroformate, Cl(CH2)2 RT 45 min 36 661 NaOH, Benzyltriethyl Clammonium chloride 267 NHCHO 4 Formic acetic anhydride, CH2Cl2 RT 5 hr 35617 DMAP 268 CH2NH(CH2 4 Ethyl bromoacetate, NaI Acetone 55 12 hr 70 776CO2Et)2 269 CH2NH(CH2 4 Isopropyl bromoacetate, Acetone 55 12 hr 67 804CO2iPr)2 NaI 270 CH2NHCH2 4 Ethyl glyoxalate, AcOH RT 1.5 hr 30 689CO2Et NaBH3CN 271 CH2NHCO(CH2)5 4 Heptanoyl chloride THF RT 12 hr 50 716CH3 272 CH2NHTosyl 4 p-Toluenesulfonyl CH2Cl2 RT 12 hr 100 757 chloride,NaHCO3 273 CH2NMeSO2iPr 4 2-propanesulfonyl CH2Cl2 RT 48 hr 47 723chloride, NaHCO3 274 CH2NHCHO 4 Formic acetic anhydride, CH2Cl2 RT 12 hr80 632 NaHCO3 275 CH2N(CH2Ph)2 4 Benzaldehyde, MeOH RT 45 min 80 784NaBH3CN, AcOH 276 CH2NHBoc 4 Di-tert-butyl CH2C12 RT 1.5 hr 40 702dicarbonate, Et3N (M − 1) 277 CH2NHCO-4- 4 4-Morpholinecarbonyl CH2Cl2RT 3 hr 42 716 morpholino chloride, Et3N, DMAP 278 CH2N(COPh) 4 PhCOCl,Et3N, DMAP CH2Cl2 RT 2 hr 72 763 (CH2)3CH3 279 CH2N(CO2Et)CH2 4 Ethylchloroformate, CH2Cl2 RT 2 hr 45 757 CF3 Et3N, DMAP 280 CH2N(CO-2- 42-Furoyl chloride, Et3N, CH2Cl2 RT 4 hr 50 753 furyl)(CH2)3CH3 DMAP 281CH2NHPh 2 and 6 Aniline — RT 72 hr 40 679 282 CH2SBu 2 and 6 BuSH,K2CO3, DMF CH2Cl2 RT 2 hr 20 676

TABLE 3 Indazole Synthesis

Temp Compound 3- Method Reagents Solvent ° C. Time Yield MH+ 301 Me 1and 6 3-methylindazole-5- CH2Cl2 RT 12 hr 50 587 sulfonyl chloride,NaHCO3 302 NH(2-Bu) 4 2-Butanone, MeOH RT 30 min. 50 644 NaBH3CN, AcOH303 NH(2-amyl) 4 2-Pentanone, MeOH RT 30 min. 50 658 NaBH3CN, AcOH 304NHcyclohexyl 4 Cyclohexanone, MeOH RT 45 min 50 670 NaBH3CN, AcOH 305NHPr 4 Propionaldehyde, MeOH RT 45 min 56 630 NaBH3CN, AcOH 306 NHCH2Ph4 Benzaldehyde, MeOH RT 45 min. 60 678 NaBH3CN, AcOH 307 NH-3-amyl 43-Pentanone, MeOH RT 45 min. 60 658 NaBH3CN, AcOH 308 NHBu 4Butyraldehyde, MeOH RT 45 min. 48 644 NaBH3CN, AcOH 309 NHCH2tBu 4Trimethylacetaldehyde, MeOH RT 45 min 50 658 NaBH3CN, AcOH 310NHCH2CO2Et 4 Ethyl bromoacetate, THF 40 3 hr 20 NaOAc 311 Cl 1 and 63-chloroindazole-5- CH2Cl2 RT 12 hr 37 607 sulfonyl chloride, NaHCO3 312NH2 5 Hydrazine EtOH 50 2 hr 70 588 313 CH2Br 1 3- CH2Cl2 RT 6 hr 75663, bromomethylindazole- 665 5-sulfonyl chloride, NaHCO3 314 NMe2 4Formaldehyde, Methanolic RT 30 min. 20 616 NaBH3CN HCl 315 N(C6H13)2 4Hexanal, NaBH3CN, MeOH RT 45 min 50 758 AcOH 316 NH2 (1-2- 42-Bromo-N,N- DMF 60 45 min. 60 687 diethylaminoethyl)diethylethylamine.HBr, K2CO3 317 NHCO2Et 4 Ethylchloroformate,ClCH2CH2Cl RT 12 hr 35 660 Et3N

TABLE 4 Synthesis of benzofuran related compounds Temp HPLC CompoundMethod Reagents Solvent ° C. Time Yield MH+ RT

401 1 NaHCO3 DCM RT 16 h 68% NMR 15.0 min

402 1 NaHCO3 DCM RT 16 h 85% NMR 15.4 min

403 Reduction of ester LiAlH4 THF RT 16 h 75% 13.5 min

404 1 NaHCO3 DCM RT 16 h 81% 603 14.1 min

405 1 NaHCO3 DCM RT 16 h 70% NMR 15.6 min

406 1 NaHCO3 DCM RT 16 h 84% 15.0 min

TABLE 5 Biological activity of Benzofurans

Ki Ki Ki IC50 IC50 IC50 WT Mutant Mutant WT Mutant Mutant9 Compound 2-3- (nM) 8 (nM) 9 (nM) (nM) 8 (nM) (nM) 101 H H <0.10 <0.30 0.50 1.6 16120 102 Me H <0.10 <0.30 0.96 3.7 90 >400 103 H Me <0.10 <0.30 0.48 3.735 300 104 CH2Br H <0.10 <0.30 0.41 8.0 41 230 105 CH2NH2 H <0.10 <0.301.9 7.0 30 220 106 CH2NHCH(Me)CO2Et H <0.10 <0.30 1.8 30 30 >400 107 HCH2NHCOMe <0.10 <0.30 0.26 15 28 42 108 H CH2-4-Morpholino <0.10 <0.301.5 1.5 38 420 109 H CH2-1-piperidino <0.10 <0.30 2.8 2.0 30 >400 110 HCH2NHBoc <0.10 <0.30 0.32 3.4 33 62 111 H CH2S(O)Bu <0.10 <0.30 0.16 8.024 49 112 H CH2NHCO2Et <0.10 <0.30 <0.10 1.8 11 29 113 H CH2NHCOEt <0.10<0.30 <0.10 7.0 20 50 114 H CH2NHCOPh 0.10 <0.30 <0.10 4.0 23 30 115 HCH2NHSO2iPr <0.10 <0.30 0.27 6.0 18 64 116 H CH2NHCbz <0.10 <0.30 0.4115 50 58 117 H CH2NH(CH2)2-2-pyridyl <0.10 <0.30 <0.10 7.0 27 49 118 HCH2NHCO-3-pyridyl <0.10 <0.30 0.12 30 35 39 119 H CH2NHCOCH2SCH2Ph 0.12<0.30 0.95 5.0 42 170 120 H CH2NHCOCH2S(O)CH2Ph <0.10 <0.30 0.22 20 31150 121 CH2NHCO2Et H <0.10 <0.30 1.6 8.0 21 >400 122 H CH2OAc <0.10<0.30 0.27 5.9 11 110 123 H CH2OMe 0.13 <0.30 0.22 4.0 19 240 124 HCH2OH <0.10 <0.30 0.26 8.7 12 130 125 H CH2NHCO-2-furanyl <0.10 <0.30<0.10 5.0 9.0 31 126 H CH2N(CO2Et)CH2CH2OMe <0.10 <0.30 0.92 4.0 60 250

TABLE 6 Biological activity of Benzisoxazoles

Ki Ki Ki IC50 IC50 IC50 WT Mutant Mutant WT Mutant Mutant Compound 3-(nM) 8 (nM) 9 (nM) (nM) 8 (nM) 9 (nM) 201 Me <0.10 <0.30 <0.10 1.8 27130 202 CH2NHiPr <0.10 <0.30 3.5 3.2 38 210 203 CH2NH2 <0.10 <0.30 0.7122 70 120 204 CH2NHSO2iPr <0.10 <0.30 0.14 6.5 31 83 205 CH2OAc <0.10<0.30 0.23 10 23 68 206 CH2CH(Me)CO2Et <0.10 <0.30 0.33 5.0 30 160 207CH2NHSO2Me <0.10 <0.30 0.34 22 28 54 208 CH2S(O)Bu <0.10 <0.30 <0.10 3.936 60 209 CH2S-iPr <0.10 <0.30 2.3 3.5 50 210 210 CH2NMeSO2Me <0.10<0.30 1.3 3.0 51 300 211 CH2NMeTs <0.10 <0.30 1.7 2.1 51 300 212CH2NHCO2iPr <0.10 <0.30 0.34 5.0 30 >400 213 CH2OH <0.10 <0.30 0.15 7.030 55 214 CH2NHCOMe <0.10 <0.30 <0.10 42 28 31 215 CH2OCOiPr <0.10 <0.300.75 11 15 55 216 CH2-1-imidazole <0.10 <0.30 1.7 20 32 250 217CH2NHCO2Et <0.10 <0.30 <0.10 2.3 30 20 218 CH2OCOtBu <0.10 <0.30 2.0 1118 80 219 CH2NHCH2 <0.10 <0.30 0.37 4.0 9.0 40 CH2OMe 220 CH2NHCOiPr<0.10 <0.30 0.14 7.0 12 60 221 CH2NHCOPh <0.10 <0.30 <0.10 7.0 14 16 222CH2NHCO2Pr <0.10 <0.30 0.19 3.0 12 45 223 CH2NHSO2Et <0.10 <0.30 0.269.0 11 60 224 CH2NH(CH2)2-2- <0.10 <0.30 0.22 15 30 100 Pyr 225CH2N((CH2)2OMe) <0.10 <0.30 0.44 3.6 27 80 CO2Et 226 CH2NHCH2CH2 <0.10<0.30 <0.10 5.5 16 38 SEt 227 CH2N((CH2)2OMe) <0.10 0.41 2.6 3.6 27 80SO2Et 228 CH2NHCH2CF2 0.12 <0.30 0.20 4.5 9.5 26 CF3 229 CH2NHCH2CF3<0.10 <0.30 0.46 2.2 3.1 21 230 CH2NHCH2CH2 <0.10 <0.30 0.14 4.8 20 57OPh 231 CH2NHBu <0.10 <0.30 0.29 4.3 23 60 232 CH2NHCH2Ph <0.10 <0.300.11 7.0 55 80 233 CH2SCH2CF3 <0.10 <0.30 3.4 4.0 36 >400 234 CH2NHCOCF3<0.10 <0.30 0.36 16 23 85 235 CH2NHcyclopentyl <0.10 <0.30 0.43 4.2 15120 236 CH2NHCH2CH2 <0.10 <0.30 0.34 6.0 18 160 NHBoc 237 CH2NH(CH2)3-1-<0.10 <0.30 0.27 31 41 85 pyrrolidine-2-one 238 CH2NHCH2cyclo <0.10<0.30 <0.10 7.5 35 55 hexyl 239 CH2-4-morpholino <0.10 <0.30 3.7 3.025 >400 240 CH2NHCO-2- <0.10 <0.30 0.26 6.5 11 20 furanyl 241CH2NHCH2-2- 0.10 <0.30 0.16 8.0 17 27 pyridyl 242 CH2NHCH2-4-(2- <0.10<0.30 0.22 7.0 15 27 methylthiazole) 243 CH2SO2Me <0.10 <0.30 0.96 8.224 120 244 CH2OCH3 <0.10 <0.30 0.49 4.1 40 305 245 CH2NHCOCF2CF3 <0.10<0.30 0.63 8.4 30 190 246 CH2OCH2CF3 <0.10 <0.30 1.1 2.7 6.8 105 247CH2N(Ac)CH2CF3 <0.10 <0.30 1.1 5.4 29 >400 248 CH2NHCH2-5- <0.10 <0.300.33 7.9 24 54 benzofuranyl

TABLE 7 Biological activity of Indazoles

Ki Ki Ki IC50 IC50 IC50 WT Mutant8 Mutant9 WT Mutant8 Mutant9 Compound3- (nM) (nM) (nM) (nM) (nM) (nM) 201 Me <0.10 <0.30 0.23 8.0 70 80 202NH(2-Bu) <0.10 <0.30 1.7 10 12 110 303 NH(2-amyl) <0.10 <0.30 0.73 10 18150 304 NHcyclohexyl <0.10 <0.30 0.93 6.1 12 100 305 NHPr <0.10 <0.300.66 16 30 180 306 NHCH2Ph 0.10 <0.30 1.1 5.5 35 95 307 NH-3-amyl <0.10<0.30 0.55 7.5 24 110 308 NHBu <0.10 <0.30 1.8 8.0 30 310 309 NHCH2tBu0.13 <0.30 3.5 4.0 25 250 310 NHCH2CO2Et <0.10 <0.30 0.19 50 70 60

TABLE 8 Biological activity of Benzofuran related compounds Ki Ki IC50IC50 IC50 Ki WT Mutant Mutant WT Mutant Mutant9 Compound (nM) 8 (nM) 9(nM) (nM) 8 (nM) (nM)

<0.10 <0.30 1.5 1.0 13 157 401

<0.10 7.5 1.5 56 900 402

<0.10 0.38 9.0 5.4 47 500 403

<0.10 0.42 4.9 3.5 42 625 404

The following examples illustrate further the present invention but, ofcourse, should not be construed in any way of limiting its scope.

EXAMPLES Example 1 Preparation of Benzofuran-5-sulfonyl chlorides

Benzofuran-5-sulfonyl chlorides may be prepared by abromination-dehydrobromination route as shown below:

2,3-Dihydrobenzofuran-5-sulfonyl chloride was prepared from commerciallyavailable 2,3-dihydrobenzofuran as described in the patent EP 0583960A2.

Preparation of benzofuran-5-sulfonyl chloride

2,3-Dihydrobenzofuran-5-sulfonyl chloride 300 mg (1.37 mmol) wasdissolved in 2 mL of benzene. N-bromosuccinimide 244 mg (1.37 mmol) and3 mg AIBN were added to the solution and the reaction was heated at 80°C. for 1 hour. The reaction was allowed to come to room temperature,filtered and the filtrate was concentrated in vacuo. The residue waspurified by chromatography on silica gel (30% CH2Cl2/hexanes) to afford237 mg (80% yield) of the pure material.

3-Methyl-2,3-dihydrobenzofuran was synthesized as described in theliterature starting from 2-iodophenol (Organic Synthesis, CV3, 418; L.W. Menapace and H. G. Kuivila, J. Amer. Chem. Soc., 86, 3047 (1964), andreferences cited therein).

3-Methyl-2,3-dihydrobenzofuran-5-sulfonyl chloride was prepared from3-methyl-2,3-dihydrobenzofuran as described in the patent EP 0583960A2.

Preparation of 2-bromo-3-bromomethyl-benzofuran-5-sulfonyl chloride (5).

3-Methyl-2,3-dihydrobenzofuran-5-sulfonyl chloride (615 mg, 2.6 mmol)was dissolved in 15 mL of benzene. N-bromosuccinimide (NBS) (471 mg, 2.6mmol) and 10 mg AIBN were added to the solution and the reaction washeated at 80° C. for 1 hour. The reaction was allowed to come to roomtemperature, and then another equivalent of NBS and AIBN were added andthe reaction was heated at 80° C. for another hour. A third equivalentof NBS and AIBN were added and the reaction was stirred at 80° C. 1 hourmore. The reaction was allowed to come to room temperature, at which itwas filtered and the solvent was removed from the filtrate in vacuo. Theresidue was purified by chromatography on silica gel (CH2Cl2-hexanesgradient 0-100%) to afford 147 mg (15% yield) of the final product.

After reaction of this material with the core the aliphatic bromine canbe displaced by nucleophiles and the 2-bromine removed by hydrogenation.

Example 2 Preparation of Indazole-5-sulfonyl chlorides

Indazole-5-sulfonyl chlorides may be prepared by directchlorosulfonylation of a protected indazole as shown below:

3-Methylindazole J. Med. Chem.; EN; 40; 17; 1997; 2706-2725

1-(3-methyl-indazol-1-yl)-ethanone

3-Methylindazole (1.00 g, 7.6 mmol) was dissolved in 10 ml THF andstirred at RT under a blanket of argon. Pyridine (0.64 ml, 7.9 mmol) wasadded followed by Ac₂O (0.79 ml, 8.3 mmol) and catalytic DMAP (90 mg,0.7 mmol). The reaction proceeded for 2 h and was then partitionedbetween 1N HCl and dichloromethane. The organic phase was dried overMgSO4 and concentrated in vacuo to a tan solid (1.2 g, 91% yield).

Ref: Chem. Ber.; 53; 1920;1204

3-Methyl-1H-indazole-5-sulfonyl chloride (3)

To chlorosulfonic acid (0.38 ml, 5.7 mmol) under a blanket of argon inan ice bath was added 1-(3-methyl-indazol-1-yl)-ethanone (200 mg, 1.1mmol). The reaction was allowed to warm to RT and then was heated at 70°C. for 45 min. The reaction was cooled to rt, slowly quenched over iceand extracted with dichloromethane. The organic phase was dried overMgSO4 and concentrated in vacuo to a tan solid (160 mg, 0.7 mmol, 61%yield).

Example 3 Preparation of Benzisoxazole-5-sulfonyl chlorides

Benzisoxazole-5-sulfonyl chlorides may be prepared by directchlorosulfonylation of a suitable substituted benzisoxazole as shownbelow:

3-Bromomethyl-benzo[d]isoxazole

Benzo[d]isoxazol-3-yl-bromo-acetic acid (J. Med. Chem. 2003, 46;5428-5436, Chem. Pharm. Bull.; EN; 26; 1978; 3498-3503) was slowlyheated under argon with stirring to 130° C. and held there for 30minutes. Copious gas evolution was observed during this time. Thereaction was cooled to RT and the resulting brown crystals were filteredoff and purified via column chromatography (hexanes), (2.3 g, 70%yield).

3-Bromomethyl-benzo[d]isoxazole-5-sulfonyl chloride

Chlorosulfonic acid (1.5 ml, 22 mmol) was slowly added to3-Bromomethyl-benzo[d]isoxazole (1.0 g, 4.7 mmol) at RT under argon. Thereaction was heated at 90° C. for 12 h and then left at RT for 6 h. Theresulting viscous oil was quenched over ice, extracted with EtOAc, driedover MgSO4 and concentrated in vacuo to a brown oil (1.17 g, 80% yield).

After reaction of this material with the core the aliphatic bromine maybe displaced by an appropriate nucleophile.

In Vitro Drug Sensitivity of HIV-1 Laboratory Isolates to PIs

The sensitivities of HIV-1 isolates against compounds of the inventionwere determined as previously described with minor modifications(Shiraska et al., Proc. Natl. Acad. Sci. USA, 92, 2398-2402 (1995)).

Any reference to any of the instant compounds also includes a referenceto a pharmaceutically acceptable salts thereof.

Any reference to any of the instant compounds also includes a referenceto a stereoisomer thereof.

Other substitutions, modifications, changes and omissions may be made inthe design, operating conditions and arrangement of the preferredembodiments without departing from the spirit of the invention asexpressed in the appended claims.

Additional advantages, features and modifications will readily occur tothose skilled in the art. Therefore, the invention in its broaderaspects is not limited to the specific details, and representativedevices, shown and described herein. Accordingly, various modificationsmay be made without departing from the spirit or scope of the generalinventive concept as defined by the appended claims and theirequivalents.

All of the references cited herein, including patents, patentapplications, and publications, are hereby incorporated in theirentireties by reference.

The claims below are not restricted to the particular embodimentsdescribed above.

1-29. (canceled)
 30. A cytochrome P450 inhibitor represented by aformula:X-A-B-A′-X′wherein: X is a 5-7 membered non-aromatic monocyclicheterocycle, wherein said heterocycle is optionally fused or bridgedwith one or more 3-7 membered non-aromatic monocyclic heterocycle toform a polycyclic system, wherein any of said heterocyclic ring systemscontains one or more heteroatoms selected from O, N, and S; wherein anynitrogen forming part of the heterocycles may optionally be substitutedby R2, R3, R6, R7 or O; wherein any sulfur may be optionally besubstituted by one or two oxygen atoms; and any of said ring systemsoptionally contains 1 to 6 substituents selected from the groupconsisting of R2, R3, R5, and R6; A is ZCZNH, ZCOCONH, ZS(O)2NH,ZP(O)(V)NH, CONH, COCONH, S(O)₂NH, P(O)(V)NH, wherein Z is NR2, O, S, orC(R2)₂, and V is OR2 or NR2; B is

wherein D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oraralkyl optionally substituted with one or more groups selected fromalkyl, halo, nitro, cyano, CF₃, C₃-C₇ cycloalkyl, C5-C7 cycloalkenyl,R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6; A′ is N(D′)E′,wherein D′ is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl,or aralkyl optionally substituted by alkyl, halo, nitro, cyano, CF₃,O-alkyl, or S-alkyl, and E′ is —CO— or —SO₂—; X′ is

wherein G1 is O and G2 is CH; wherein Z′″ is selected from the groupconsisting of H, R2, R3, R6, haloalkyl, C(R2)₂OR, C(R2)₂COR, C(R2)₂OCOR,C(R2)₂CO₂R, C(R2)₂N(R)₂, C(R2)₂SOR, and C(R2)₂SO₂R; wherein X′ isoptionally substituted with one or more substituents, each independentlyselected from (a)-(h) as follows: (a) OR3, OR6, OR7, OR2; (b) alkylsubstituted by R3, R5, R6; (c) C2-C6 alkenyl, C2-C6 alkynyl, C3-C8cycloalkyl, C5-C8 cycloalkenyl, and heterocyclyl, which groups may beoptionally substituted with one or more substituents selected from R5;(d) aryl or heteroaryl, wherein said aryl or heteroaryl may beoptionally substituted with one or more groups selected from the groupconsisting of aryl, heteroaryl, R2, R3, R4 and R6; (e) C3-C7 cycloalkylsubstituted by R2, R3, R5 or R6; (f) CO₂H or R7; (g) NR8R8, NR7R8,NR7R7; and (h) SO_(n)N(R8)₂, SO_(n)NR7R8, SR8, S(O)_(n)R8; and n is 1 or2; R is H or is selected from the group consisting of alkyl, aryl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo and heteroaryl;optionally substituted by halo, hydroxy, alkoxy, aryloxy, cycloalkoxy,heteroaryloxy, cyano, nitro, alkylthio, arylthio, cycloalkylthio, amino,or mono- or dialkylamino, mono- or diarylamino, mono- ordi-cycloalkylamino, mono- or di-heteroarylamino, alkanoyl,cycloalkanoyl, aroyl, heteroaroyl, carboxamido, mono ordialkylcarboxamido, mono- or diarylcarboxamido, sulfonamido, mono- ordialkylsulfonamido, mono- or diarylsulfonamido, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, cycloalkylsulfinyl,cycloalkylsulfonyl, heteroarylsulfinyl, heteroarylsulfonyl; R2 is H orC1-C6 alkyl; optionally substituted by C2-C6 alkenyl, C2-C6 alkynyl,C3-C8 cycloalkyl, C5-C8 cycloalkenyl, heterocyclo; which groups may beoptionally substituted with one or more substituents selected from thegroup consisting of halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂,C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SR, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R); or R2 is C1-C₆ alkyl; substitutedby aryl or heteroaryl; which groups may be optionally substituted withone or more substituents selected from the group consisting of halo, OR,ROH, R-halo, NO₂, CN, CO_(n)R, CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂,SO_(n)R, N(R)₂, N(R)CO_(n)R, NRS(O)_(n)R, NRC[═N(R)]N(R)₂,N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂, NRPO_(n)OR; or R2 is C1-C6 alkyl;optionally substituted by halo, OR, ROH, R-halo, NO₂, CN, CO_(n)R,CON(R)₂, C(S)R, C(S)N(R)₂, SO_(n)N(R)₂, SO_(n)R, N(R)₂, N(R)CO_(n)R,NRS(O)_(n)R, NRC[═N(R)]N(R)₂, N(R)N(R)CO_(n)R, NRPO_(n)N(R)₂,NRPO_(n)OR, oxo, ═N—OR, ═N—N(R)₂, ═NR, ═NNRC(O)N(R)₂, ═NNRCO_(n)R,═NNRS(O)_(n)N(R)₂, or ═NNRS(O)_(n)(R); R3 is C2-C6 alkenyl, C2-C6alkynyl, C3-C8 cycloalkyl, C5-C8 cycloalkenyl, or heterocyclo; whichgroups may be optionally substituted with one or more substituentsselected from the group consisting of halo, OR2, R2-OH, R2-halo, NO₂,CN, CO_(n)R2, C(O)N(R2)₂, C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂,S(O)nN(R2)₂, SR2, SO_(n)R2, N(R)₂, N(R2)CO_(n)R2, NR2S(O)_(n)R,NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2, NR2PO_(n)N(R2)₂, NR2PO_(n)OR2,oxo, ═N—OR2, ═N—N(R2)₂, ═NR2, ═NNRC(O)N(R2)₂, ═NNR2C(O)_(n)R2,═NNR2S(O)_(n)N(R2)₂, or ═NNR2S(O)_(n)(R2); R4 is selected from the groupconsisting of halo, OR8, R2-OH, R3-OH, R2-halo, R3-halo, NO₂, CN,CO_(n)R8, CO_(n)R8, CON(R8)₂, C(O)N(R8)N(R8)₂, C(S)R8, C(S)N(R8)₂,SO_(n)N(R8)₂, SR8, SO_(n)R8, N(R8)₂, N(R8)CO_(n)R8, NR8S(O)_(n)R8,NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)CO_(n)R8, NR8PO_(n)N(R8)₂, NR8PO_(n)OR8,OC(O)R2, OC(S)R8, OC(O)N(R8)₂, OC(S)N(R8)₂ and OPO_(n)(R8)₂; R5 isselected from the group consisting of OR8, N(R8)₂, NHOH, N(R8)COR8,NR8S(O)_(n)R8, NR8C[═N(R8)]N(R8)₂, N(R8)N(R8)C(O)R8, NR8PO_(n)N(R8)₂,NR8PO_(n)OR8, R2OH, R3-OH, R2-halo, R3-halo, CN, CO_(n)R8; CON(R8)₂,C(O)N(R8)N(R8)₂, C(S)_(n)R8, C(S)N(R8)₂, S(O)_(n)R8, SO_(n)N(R8)₂, halo,NO₂, SR8, oxo, ═N—OH, ═N—OR8, ═N—N(R8)₂, ═NR8, ═NNR8C(O)N(R8)₂,═NNR8C(O)_(n)R8, ═NNR8S(O)_(n)N(R8)₂, or ═NNR8S(O)_(n)(R8) and R3; R6 isaryl or heteroaryl, wherein said aryl or heteroaryl may be optionallysubstituted with one or more groups selected from aryl, heteroaryl, R2,R3, halo, OR2, R2OH, R2-halo, NO₂, CN, CO_(n)R2, C(O)N(R2)₂,C(O)N(R2)N(R2)₂, C(S)R2, C(S)N(R2)₂, S(O)_(n)N(R2)₂, SO_(n)R2, N(R)₂,N(R2)CO_(n)R2, NR2S(O)_(n)R2, NR2C[═N(R2)]N(R2)₂, N(R2)N(R2)CO_(n)R2,NR2PO_(n)N(R2)₂, NR2PO_(n)OR2, OC(O)R2, OC(S)R2, OC(O)N(R2)₂,OC(S)N(R2)₂, and OPO_(n)(R2)2; R7 is selected from the group consistingof C(O)_(n)R8; C(S)R8, C(O)N(R8)₂, C(S)N(R8)₂, S(O)_(n)R8 andS(O)nN(R8)₂; R8 is R2, R3, or R6; R9 is alkyl optionally substituted byR3, R5, R6; C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C5-C8cycloalkenyl, and heterocyclo, which groups may be optionallysubstituted with one or more substituents selected from the groupconsisting of —OR2, C(O)N(R2)₂, S(O)_(n)N(R2)₂, CN, SO_(n)R2, COR2,CO₂R2 or NR2C(O)R2, R5, and R7; aryl and heteroaryl, wherein said arylor heteroaryl may be optionally substituted with one or more groupsselected from the group consisting of aryl, heteroaryl, R2, R3, R4, andR6; C3-C7 cycloalkyl optionally substituted by R2, R3, R5, R6; CO₂H orR7; NR3R3, NR6R6, NR7R7, NR3R6, NR6R7, NR3R7, NR2R3, NR2R6, NR2R7,NR2R2; SO_(n)N(R8)₂, SO_(n)NR7R8, S(O)_(n)R8; and n is 1 or 2;SO_(n)N(R2)₂, SO_(n)N(R3)₂, SO_(n)N(R6)₂, SO_(n)N(R7)₂, SO_(n)NR2R3,SO_(n)NR2R6, SO_(n)NR2R7; SO_(n)NR3R6, SO_(n)NR3R7, SO_(n)NR6R7;S(O)_(m)R2, S(O)_(m)R3, S(O)_(m)R6; and m is 0, 1 or 2; and each n isindependently 1 or
 2. 31. The inhibitor according to claim 30, whereinZ′″ is R2.
 32. The inhibitor according to claim 31, wherein R2 is H orC1-C6 alkyl optionally substituted by halo.
 33. The inhibitor accordingto claim 32, wherein R2 is H.
 34. The inhibitor according to claim 30,wherein X is

Y and Z are O; and wherein any ring carbon is optionally substituted byR2, R3, R5, or R6.
 35. The compound of claim 30, wherein X is

wherein G is C, O, or NR2; n is an integer between 1-2; and wherein anyring carbon is optionally substituted by R2, R3, R5, or R6.
 36. Theinhibitor according to claim 30, wherein X istetrahydrofurodihydrofuranyl, tetrahydrofurotetrahydrofuranyl,tetrahydropyranotetrahydrofuranyl or tetrahydropyranodihydrofuranyl; Ais OCONH; B is

wherein D is selected from alkyl, alkenyl, alkynyl, aryl, cycloalkyl, oraralkyl optionally substituted with one or more groups selected fromalkyl, halo, nitro, cyano, CF₃, C3-C7 cycloalkyl, C5-C7 cycloalkenyl,R6, OR2, SR2, NHR2, OR3, SR3, NHR3, OR6, SR6, or NHR6; and A′ isN(D′)E′, wherein D′ is alkyl, alkenyl, alkynyl aryl, cycloalkyl, oraralkyl optionally substituted by alkyl, halo, or CF₃, and E′ is —SO₂—.37. The HIV protease inhibitor of claim 30, wherein: X istetrahydrofurotetrahydrofuranyl; A is OCONH; B is

wherein D is benzyl; and A′ is N(D′)E′, wherein D′ is isobutyl and E′ is—SO₂—;
 38. The inhibitor according to claim 30, wherein: X is

wherein A3 is H, F or alkoxy; B3 is F, alkoxy, lower alkyl, or A3 and B3can form a 3-7 membered heterocyclic ring; Z′ is O, NR2, or S; and n isan integer between 1-3.
 39. The inhibitor of claim 30, wherein Z′″ isselected from the group consisting of H, Me, CH2OH, CH2OAc, CH2OMe,CH2NHiPr, CH2NH2, CH2S(O)Bu, CH2S-iPr, CH2OCOtBu, CH2NHCH2CH2OMe,CH2NHCOiPr, CH2NHCOPh, CH2NHCO2Pr, CH2NHCOMe, CH2-4-Morpholino,CH2-1-piperidino, CH2NHBoc, CH2NHCO2Et, CH2NHCOEt, CH2NHSO2iPr,CH2NHCbz, CH2NH(CH2)2-2-pyridyl, CH2NHCO3-pyridyl, CH2NHCOCH2SCH2Ph,CH2NHCOCH2S(O)CH2Ph, CH2NHCO-2-furanyl, CH2N(CO2Et)CH2CH2OMe,NHCH(Me)CO2Et, CH2NHSO2Et, CH2NHSO2Me, CH2NMeSO2Me, CH2NMeTs,CH2NHCO2iPr, CH2OCOiPr, CH2-1-imidazole, CH2NHCH2CH2SEt,CH2N((CH2)2OMe)SO2Et, CH2NHCH2CF2CF3, CH2NHCH2CF3, CH2NHCH2CH2OPh,CH2NHBu, CH2NHCH2Ph, CH2SCH2CF3, CH2NHCOCF3, CH2NHcyclopentyl,CH2NHCH2CH2NHBoc, CH2NH(CH2)3-1-pyrrolidine-2-one, CH2NHCH2cyclohexyl,CH2NHCH2-2-pyridyl, CH2NHCH2-4-(2-methylthiazole), CH2SO2Me,CH2NHCOCF2CF3, CH2OCH2CF3, CH2N(Ac)CH2CF3, and CH2NHCH2-5-benzofuranyl.40. A pharmaceutical composition comprising an effective amount of aninhibitor according to claim 30 and a pharmaceutically acceptableadditive, excipient, or diluent.
 41. A pharmaceutical compositioncomprising an effective amount of an inhibitor according to claim 30 andan agent that is metabolized by a cytochrome P450.
 42. A pharmaceuticalcomposition according to claim 41 wherein said agent is an HIVinhibitor.
 43. The composition according to claim 42 wherein said HIVinhibitor is an HIV protease inhibitor.
 44. The composition according toclaim 42 wherein said HIV inhibitor is an HIV reverse transcriptaseinhibitor.
 45. A method of inhibiting metabolic degradation of a drug ina subject being treated with said drug, comprising administering to thesubject a degradation-inhibiting amount of a compound of claim
 30. 46.The method of claim 45, wherein said compound is administeredsubstantially contemporaneously with said drug.
 47. The method of claim45, wherein said compound is administered prior to administration ofsaid drug.